Chimeric oncolytic adenovirus evades neutralizing antibodies from human patients and exhibits enhanced anti-glioma efficacy in immunized mice.

Oncolytic viruses are a promising treatment for patients with high-grade gliomas, but neutralizing antibodies can limit their efficacy in patients with prior virus exposure or upon repeated virus injections. Data from a previous clinical trial using the oncolytic adenovirus Delta-24-RGD showed that generation of anti-viral neutralizing antibodies may affect the long-term survival of glioma patients. Past studies have examined the effects of neutralizing antibodies during systemic virus injections, but largely overlooked their impact during local virus injections into the brain. We found that immunoglobulins colocalized with viral proteins upon local oncolytic virotherapy of brain tumors, warranting a strategy to prevent virus neutralization and maximize oncolysis. Thus, we generated a chimeric virus, Delta-24-RGD-H43m, by replacing the capsid protein HVRs from the serotype 5-based Delta-24-RGD with those from the rare serotype 43. Delta-24-RGD-H43m evaded neutralizing anti-Ad5 antibodies and conferred a higher rate of long-term survival than Delta-24-RGD in glioma-bearing mice. Importantly, Delta-24-RGD-H43m activity was significantly more resistant to neutralizing antibodies present in sera of glioma patients treated with Delta-24-RGD during a phase 1 clinical trial. These findings provide a framework for a novel treatment of glioma patients that have developed immunity against Delta-24-RGD.

Systemic inflammation, enteropathogenic E. Coli, and micronutrient insufficiencies in the first trimester as possible predictors of preterm birth in rural Bangladesh: a prospective study.

BACKGROUND: An incomplete understanding of preterm birth is especially concerning for low-middle income countries, where preterm birth has poorer prognoses. While systemic proinflammatory processes are a reportedly normal component of gestation, excessive inflammation has been demonstrated as a risk factor for preterm birth. There is minimal research on the impact of excessive maternal inflammation in the first trimester on the risk of preterm birth in low-middle income countries specifically. METHODS: Pregnant women were enrolled at the rural Bangladesh site of the National Institute of Child Health Global Network Maternal Newborn Health Registry. Serum samples were collected to measure concentrations of the inflammatory markers C-reactive protein (CRP) and Alpha-1-acid glycoprotein (AGP), and stool samples were collected and analyzed for enteropathogens. We examined associations of maternal markers in the first-trimester with preterm birth using logistic regression models. CRP and AGP were primarily modeled with a composite inflammation predictor. RESULTS: Out of 376 singleton births analyzed, 12.5% were preterm. First trimester inflammation was observed in 58.8% of all births, and was significantly associated with increased odds of preterm birth (adjusted odds ratio [aOR] = 2.23; 95% confidence interval [CI]: 1.03, 5.16), independent of anemia. Maternal vitamin B12 insufficiency (aOR = 3.33; 95% CI: 1.29, 8.21) and maternal anemia (aOR = 2.56; 95% CI: 1.26, 5.17) were also associated with higher odds of preterm birth. Atypical enteropathogenic E. coli detection showed a significant association with elevated AGP levels and was significantly associated with preterm birth (odds ratio [OR] = 2.36; 95% CI: 1.21, 4.57), but not associated with CRP. CONCLUSIONS: Inflammation, anemia, and vitamin B12 insufficiency in the first trimester were significantly associated with preterm birth in our cohort from rural Bangladesh. Inflammation and anemia were independent predictors of premature birth in this low-middle income setting where inflammation during gestation was widespread. Further research is needed to identify if infections such as enteropathogenic E. coli are a cause of inflammation in the first trimester, and if intervention for infection would decrease preterm birth.

Missed Opportunities for Screening or Surveillance Among Patients with Newly Diagnosed Non-cardia Gastric Adenocarcinoma.

BACKGROUND: Screening for gastric cancer is not recommended despite rising rates in certain U.S. POPULATIONS: We determined possible missed opportunities for the detection and surveillance of preneoplastic lesions among gastric cancer patients in a VA hospital. METHODS: This retrospective cohort study included consecutive, newly diagnosed non-cardia gastric adenocarcinoma patients from 11/2007 to 10/2018 at the Houston VA Hospital. We identified missed opportunities for screening based on risk factors (non-White race, smoking, alcohol, Helicobacter pylori infection, gastric ulcers, family history of gastric cancer). We additionally determined missed opportunities for surveillance of known high-risk lesions. Associations between receipt of prior endoscopy for screening or surveillance and cancer-related outcomes (stage, treatment, survival) were determined using logistic regression models. RESULTS: Among 91 gastric cancer patients, 95.6% were men, 51.6% were black, 12.1% were Hispanic, with mean age of 68.0 years (standard deviation 10.8 years). The most common risk factors included non-white race (68.1%), smoking (76.9%), alcohol use (59.3%) and prior H. pylori (12.1%). Most patients had ≥ 1 risk factor for gastric cancer (92.6%), and 76.9% had ≥ 2 risk factors. Only 25 patients (27.5%) had undergone endoscopy prior to cancer diagnosis. Of 14 with known high-risk lesions (i.e., gastric intestinal metaplasia, dysplasia, ulcer), only 2 (14.3%) underwent surveillance endoscopy. Receipt of prior endoscopy was not associated with differences in cancer outcomes. CONCLUSIONS: Most patients with newly diagnosed gastric cancer had ≥ 2 known risk factors for gastric cancer but never received prior screening endoscopy. Among the few with known prior preneoplastic lesions, endoscopic surveillance was not consistently performed.

Inking outside the box: systematic review on the utility of tattooing lesions in rectal cancer.

PURPOSE: Endoscopic tattooing in rectal cancer is infrequently utilized for fear of tattoo ink obscuring anatomical planes, increasing the difficulty of surgical excision. Colon cancer tattooing has demonstrated increased lymph node yields and increased accuracy in establishing adequate margins. Rectal cancer tattooing may be especially helpful after neoadjuvant chemoradiation, where complete clinical responses could limit lesion identification and lymph node yields are typically less robust. We seek to review and identify the effects of tattooing in rectal cancer. METHODS: A systematic literature search was performed in PubMed, Embase, and SCOPUS. Studies on endoscopic tattooing with cohorts consisting of at least ≥ 25% of rectal cancer patients were selected. Studies focusing solely on rectal cancer were also reviewed separately. RESULTS: Of 416 studies identified, 10 studies encompassing 2460 patients were evaluated. Seven studies evaluated lymph node yields; five reported beneficial effects of endoscopic tattooing, while two reported no significant difference. Among four studies reporting lesion localization, successful localization rates were between 63 and 100%. Rates of intraoperative endoscopy performed to reevaluate lesion location ranged from 5.7 to 20%. The distal margin was evaluated in two studies, which reported more accurate placement of the distal resection margin after tattooing. When complications of tattooing were documented (7 studies with 889 patients), only five direct complications of endoscopic tattooing were observed (0.6%). CONCLUSIONS: Although the data is heterogenous, it suggests that endoscopic tattooing in rectal cancer may improve lymph node yields and assist in determining accurate distal margins without high rates of complication. Further research must be completed before practice management guidelines can change. TRIAL REGISTRATION: No. CRD42021271784.

Histone deacetylase inhibitor, suberoylanilide hydroxamic acid (SAHA), enhances anti-tumor effects of the poly (ADP-ribose) polymerase (PARP) inhibitor olaparib in triple-negative breast cancer cells.

INTRODUCTION: Olaparib, a poly (ADP-ribose) polymerase (PARP) inhibitor, has been found to have therapeutic potential for treating cancers associated with impaired DNA repair capabilities, particularly those with deficiencies in the homologous recombination repair (HRR) pathway. Histone deacetylases (HDACs) are important for enabling functional HRR of DNA by regulating the expression of HRR-related genes and promoting the accurate assembly of HRR-directed sub-nuclear foci. Thus, HDAC inhibitors have recently emerged as a therapeutic agent for treating cancer by inhibiting DNA repair. Based on this, HDAC inhibition could be predicted to enhance the anti-tumor effect of PARP inhibitors in cancer cells by blocking the HRR pathway. METHODS: We determined whether suberoylanilide hydroxamic acid (SAHA), a HDAC inhibitor, could enhance the anti-tumor effects of olaparib on breast cancer cell lines using a cytotoxic assay, cell cycle analysis, and Western blotting. We evaluated how exposure to SAHA affects the expression of HRR-associated genes. The accumulation of DNA double strand breaks (DSBs) induced by combination treatment was assessed. Induction of autophagy was monitored by imaging green fluorescent protein-tagged microtubule-associated protein 1A/1B-light chain 3 (LC3) expression following co-treatment with olaparib and SAHA. These in vitro data were validated in vivo using a human breast cancer xenograft model. RESULTS: Triple-negative breast cancer cell (TNBC) lines showed heterogeneous responses to the PARP and HDAC inhibitors. Co-administration of olaparib and SAHA synergistically inhibited the growth of TNBC cells that expressed functional Phosphatase and tensin homolog (PTEN). This effect was associated with down-regulation of the proliferative signaling pathway, increased apoptotic and autophagic cell death, and accumulation of DNA damage. The combined anti-tumor effect of olaparib and SAHA was also observed in a xenograft model. These data suggest that PTEN expression in TNBC cells can sensitize the cell response to simultaneous inhibition of PARP and HDAC both in vitro and in vivo. CONCLUSION: Our findings suggest that expression of functional PTEN may serve as a biomarker for selecting TNBC patients that would favorably respond to a combination of olaparib with SAHA. This provides a strong rationale for treating TNBC patients with PTEN expression with a combination therapy consisting of olaparib and SAHA.

PSA Levels and Mortality in Prostate Cancer Patients.

INTRODUCTION: Prostate cancer (PC) is the second most common cancer among men around the world. Several smaller studies have explored the relationship between elevated PSA and mortality, but results have been conflicting. Additionally, studies have shown that Black men are more likely to be diagnosed with PC at late-stages and may have a twofold increase in mortality risk. This study aims to evaluate the relationship between PSA levels and mortality in patients with PC and differences between Black versus White patients. METHODS: In this retrospective study, the TriNetX database, was used to extract de-identified EMRs of 198,083 patients. Patients were included if they were diagnosed with PC and had obtained a PSA level (measured in ng/mL) within 6 months prior to diagnosis. Cohorts were separated into 7 groups based on intervals of PSA, ranging from < 2 to ≥ 500 and compared to a control cohort with a PSA of 4 to 20 for differing 2-year mortality rates. A subgroup analysis was performed to compare mortality differences between Black and White patients. A posthoc analysis evaluated 5- and 10-year mortality amongst all patients with PC. RESULTS: After propensity matching, mortality risk was significantly lower for patients with PSA < 2 (5.9% vs. 7.5%; RR 0.784; P < .001) when compared to the control cohort. Mortality was significantly higher for all other subsequent PSA intervals > 20, with the lowest risk ratios at PSA 20-100 (24.1% vs. 10.0%; RR 2.419; P < .001) and highest at PSA 200 to 500 (50.4% vs. 10.8%; RR 4.673; P < .001). The sub-group analysis showed that when compared to White patients, Black patients with PSA < 20 had similar mortalities, but had significantly lower 2-year mortality rates at PSA levels ≥ 20. The posthoc analysis of PSA levels and 5- and 10-year mortality of all patients with PC showed similar trends to the 2-year outcomes. CONCLUSION: This study found that prostate cancer patients with significantly elevated PSA levels have a greater mortality, and Black patients have lower 2-year mortality rates than their White counterparts when matched for PSA levels greater than 20.

Less neutralization evasion of SARS-CoV-2 BA.2.86 than XBB sublineages and CH.1.1.

The highly mutated BA.2.86, with over 30 spike protein mutations in comparison to Omicron BA.2 and XBB.1.5 variants, has raised concerns about its potential to evade COVID-19 vaccination or prior SARS-CoV-2 infection-elicited immunity. In this study, we employ a live SARS-CoV-2 neutralization assay to compare the neutralization evasion ability of BA.2.86 with other emerged SARS-CoV-2 subvariants, including BA.2-derived CH.1.1, Delta-Omicron recombinant XBC.1.6, and XBB descendants XBB.1.5, XBB.1.16, XBB.2.3, EG.5.1 and FL.1.5.1. Our results show that BA.2.86 is less neutralization evasive than XBB sublineages. XBB descendants XBB.1.16, EG.5.1, and FL.1.5.1 continue to significantly evade neutralization induced by the parental COVID-19 mRNA vaccine and a BA.5 Bivalent booster. Notably, when compared to XBB.1.5, the more recent XBB descendants, particularly EG.5.1, display increased resistance to neutralization. Among all the tested variants, CH.1.1 exhibits the greatest neutralization evasion. In contrast, XBC.1.6 shows a slight reduction but remains comparably sensitive to neutralization when compared to BA.5. Furthermore, a recent XBB.1.5-breakthrough infection significantly enhances the breadth and potency of cross-neutralization. These findings reinforce the expectation that the upcoming XBB.1.5 mRNA vaccine would likely boost the neutralization of currently circulating variants, while also underscoring the critical importance of ongoing surveillance to monitor the evolution and immune evasion potential of SARS-CoV-2 variants.

High-strength cellulose nanofiber/graphene oxide hybrid filament made by continuous processing and its humidity monitoring.

Human-made natural-fiber-based filaments are attractive for natural fiber-reinforced polymer (NFRP) composites. However, the composites' moisture distribution is critical, and humidity monitoring in the NFRP composites is essential to secure stability and keep their life span. In this research, high strength and humidity sensing filament was developed by blending cellulose nanofiber (CNF) and graphene oxide (GO), wet-spinning, coagulating, and drying, which can overcome the heterogeneous mechanical properties between embedded-type humidity sensors and NFRP composites. The stabilized synthesis process of the CNF-GO hybrid filament demonstrated the maximum Young's modulus of 23.9 GPa and the maximum tensile strength of 439.4 MPa. Furthermore, the achieved properties were successfully transferred to a continuous fabrication process with an additional stretching process. Furthermore, its humidity sensing behavior is shown by resistivity changes in various temperature and humidity levels. Therefore, this hybrid filament has excellent potential for in-situ humidity monitoring by embedding in smart wearable devices, natural fiber-reinforced polymer composites, and environmental sensing devices.

Androgen Receptor Inhibitor Enhances the Antitumor Effect of PARP Inhibitor in Breast Cancer Cells by Modulating DNA Damage Response.

The androgen receptor (AR) is expressed in 60%-70% of breast cancers regardless of estrogen receptor status, and has been proposed as a therapeutic target in breast cancers that retain AR. In this study, the authors aimed to investigate a new treatment strategy using a novel AR inhibitor AZD3514 in breast cancer. AZD3514 alone had a minimal antiproliferative effect on most breast cancer cell lines irrespective of AR expression level, but it downregulated the expressions of DNA damage response (DDR) molecules, including ATM and chk2, which resulted in the accumulation of damaged DNA in some breast cancer cells. Furthermore, AZD3514 enhanced cellular sensitivity to a PARP inhibitor olaparib by blocking the DDR pathway in breast cancer cells. Furthermore, the downregulation of NKX3.1 expression in MDA-MB-468 cells by AZD3514 occurred in parallel with the suppression of ATM-chk2 axis activation, and the suppression of NKX3.1 by AZD3514 was found to result from AZD3514-induced TOPORS upregulation and a resultant increase in NKX3.1 degradation. The study shows posttranslational regulation of NKX3.1 via TOPORS upregulation by AZD3514-induced ATM inactivation-increased olaparib sensitivity in AR-positive and TOPORS-expressing breast cancer cells, and suggests the antitumor effect of AZD3514/olaparib cotreatment is caused by compromised DDR activity in breast cancer cell lines and in a xenograft model. These results provide a rationale for future clinical trials of olaparib/AR inhibitor combination treatment in breast cancer.

Performance improvement of miniaturized ZnO nanowire accelerometer fabricated by refresh hydrothermal synthesis.

Miniaturized accelerometers are necessary for evaluating the performance of small devices, such as haptics, robotics and simulators. In this study, we fabricated miniaturized accelerometers using well-aligned ZnO nanowires. The layer of ZnO nanowires is used for active piezoelectric layer of the accelerometer, and copper was chosen as a head mass. Seedless and refresh hydrothermal synthesis methods were conducted to grow ZnO nanowires on the copper substrate and the effect of ZnO nanowire length on the accelerometer performance was investigated. The refresh hydrothermal synthesis exhibits longer ZnO nanowires, 12 µm, than the seedless hydrothermal synthesis, 6 µm. Performance of the fabricated accelerometers was verified by comparing with a commercial accelerometer. The sensitivity of the fabricated accelerometer by the refresh hydrothermal synthesis is shown to be 37.7 pA g-1, which is about 30 times larger than the previous result.

AZD6738, A Novel Oral Inhibitor of ATR, Induces Synthetic Lethality with ATM Deficiency in Gastric Cancer Cells.

Ataxia telangiectasia and Rad3-related (ATR) can be considered an attractive target for cancer treatment due to its deleterious effect on cancer cells harboring a homologous recombination defect. The aim of this study was to investigate the potential use of the ATR inhibitor, AZD6738, to treat gastric cancer.In SNU-601 cells with dysfunctional ATM, AZD6738 treatment led to an accumulation of DNA damage due to dysfunctional RAD51 foci formation, S phase arrest, and caspase 3-dependent apoptosis. In contrast, SNU-484 cells with functional ATM were not sensitive to AZD6738. Inhibition of ATM in SNU-484 cells enhanced AZD6738 sensitivity to a level comparable with that observed in SNU-601 cells, showing that activation of the ATM-Chk2 signaling pathway attenuates AZD6738 sensitivity. In addition, decreased HDAC1 expression was found to be associated with ATM inactivation in SNU-601 cells, demonstrating the interaction between HDAC1 and ATM can affect sensitivity to AZD6738. Furthermore, in an in vivo tumor xenograft mouse model, AZD6738 significantly suppressed tumor growth and increased apoptosis.These findings suggest synthetic lethality between ATR inhibition and ATM deficiency in gastric cancer cells. Further clinical studies on the interaction between AZD 6738 and ATM deficiency are warranted to develop novel treatment strategies for gastric cancer. Mol Cancer Ther; 16(4); 566-77. ©2017 AACR.

Amphiregulin confers trastuzumab resistance via AKT and ERK activation in HER2-positive breast cancer.

PURPOSE: Human epidermal growth factor receptor 2 (HER2) heterodimerizes and shares common signaling pathways with epidermal growth factor receptor (EGFR). In this study, we investigated the clinical implication of amphiregulin, a ligand for EGFR, on trastuzumab therapy in HER2-positive breast cancer. METHODS: Serum amphiregulin levels were quantified in 50 consecutive patients with HER2-positive metastatic breast cancer who received first-line trastuzumab plus taxane chemotherapy between October 2004 and July 2009. In addition, in vitro experiments were carried out to validate the results. RESULTS: The median serum amphiregulin level was 1.0 ng/mL with a maximum level of 4.4 ng/mL. Patients with high serum amphiregulin levels (≥0.5 ng/mL) had significantly shorter progression-free survival (15.1 months vs. not reached; P = 0.018). Colony-forming assays demonstrated that the addition of amphiregulin resulted in increased proliferation of cells. In addition, the anti-proliferative effect of trastuzumab was decreased in the presence of amphiregulin. Western blot analysis showed that amphiregulin activated AKT and ERK pathways. In addition, in the presence of amphiregulin, sustained phosphorylation of AKT and ERK pathways was observed after trastuzumab treatment. CONCLUSIONS: High serum amphiregulin levels were associated with early disease progression in these patients, possibly due to AKT and ERK signaling activation by amphiregulin.

A phased consent policy for cord blood donation.

This article focuses on ethical and policy questions concerning when consent may be sought for the collection and donation of cord blood. It reviews the advantages and disadvantages of alternative times for securing consent, challenges common objections to seeking consent during labor or after collection, and describes a phased consent process--a process that permits consent during early labor to the ex utero collection of cord blood followed by after-consent collection to donation. The phased consent policy attends to the unique characteristics of cord blood collection and donation, respects donors and their families, maximizes the number and diversity of cord blood units collected, preserves the relationship between providers and patients, and preserves public trust in cord blood and other types of tissue banking.