Development of FAP-Targeted Chimeric Antigen Receptor NK-92 Cells for Non-Small Cell Lung Cancer.

OBJECTIVES: Over the past two decades, great progress has been made in advancing the early detection and multimodal treatment of non-small cell lung cancer (NSCLC). However, overall cure rates and survival rates of NSCLC are still not satisfactory, and research into new therapies is needed. This study attempted to construct human Fibroblast Activation Protein-Chimeric Antigen Receptor Natural killer (NK)-92 cells (hFAP-CAR-NK-92 cells) and explore their potential therapeutic effects in NSCLC. METHODS: Immunohistochemistry analysis was carried out to examine fibroblast activation protein (FAP) and Gasdermin E (GSDME) expression in clinical specimens of lung adenocarcinoma and squamous cell carcinoma tissue. Then the engineered hFAP-CAR-NK-92 cells efficiency was determined in vitro with lactate dehydrogenase (LDH) cytotoxicity assay and the cell morphology of A549, H226, and cancer-related fibroblast (CAF) was observed by electron microscopy. After the co-culture of target cells and effect cells, flow cytometry was employed for examining the CD107a expression in the effect cells, and western blotting was conducted for the cleavage levels of Caspase 3 and GSDME proteins in the target cells. The safety and efficacy of hFAP-CAR-NK-92 cells adoptive transfer immunotherapy in a tumor-bearing mouse were evaluated. RESULTS: Clinical studies have shown FAP positivity in patients with NSCLC. Compared with A549 or H226 cells alone, FAP expression was notably raised in A549+CAF cells or H226+CAF cells in nude mice, respectively (p < 0.05). The killing efficiency of K562 cells was not significantly different between hFAP-CAR-NK-92 and NK-92 cells (p > 0.05). The hFAP-CAR-NK-92 cells presented a higher killing efficiency against the hFAP-target (A549-hFAP, H226-hFAP and CAF-hFAP) cells than the NK-92 cells (p < 0.05). The degranulation of CD107a and cleavage levels of GSDME and Caspase 3 protein in the hFAP-CAR-NK-92 group were higher than those in the NK-92 group (p < 0.05). The 300 nM Granzyme B also induced pyroptosis in hFAP- or GSDME-positive cells (p < 0.05). In vivo experiments revealed that hFAP-CAR-NK-92 cells inhibited tumor progression of hFAP-positive NSCLC (p < 0.05). CONCLUSIONS: In this study, we successfully constructed hFAP-CAR-NK-92 cells and confirmed that hFAP-CAR-NK-92 cells could target hFAP-positive NSCLC to inhibit the progression of NSCLC by activating the Caspase-3/GSDME pyroptosis pathway.

Radiation use efficiency increased over a century of maize (Zea mays L.) breeding in the US corn belt.

In the absence of stress, crop growth depends on the amount of light intercepted by the canopy and the conversion efficiency [radiation use efficiency (RUE)]. This study tested the hypothesis that long-term genetic gain for grain yield was partly due to improved RUE. The hypothesis was tested using 30 elite maize hybrids commercialized in the US corn belt between 1930 and 2017. Crops grown under irrigation showed that pre-flowering crop growth increased at a rate of 0.11 g m-2 year-1, while light interception remained constant. Therefore, RUE increased at a rate of 0.0049 g MJ-1 year-1, translating into an average of 3 g m-2 year-1 of grain yield over 100 years of maize breeding. Considering that the harvest index has not changed for crops grown at optimal density for the hybrid, the cumulative RUE increase over the history of commercial maize breeding in the USA can account for ~32% of the documented yield trend for maize grown in the central US corn belt. The remaining RUE gap between this study and theoretical maximum values suggests that a yield improvement of a similar magnitude could be achieved by further increasing RUE.

Adverse events associated with venomous insect immunotherapy and clinical outcomes in 82 dogs (2002-2020).

BACKGROUND: Limited information is known on adverse events and efficacy associated with venomous insect immunotherapy (VIT) in canine patients. OBJECTIVES: To assess adverse events associated with VIT and perceived efficacy of VIT. ANIMALS: Records from 82 client-owned animals which received VIT were assessed. METHODS AND MATERIALS: A retrospective review of records from 2002 to 2020. Clinical history, adverse events during therapy and observations following field stings were collected from all records. Patients were grouped into reactors and nonreactors based on whether or not an adverse event had occurred during therapy. Records were evaluated to determine if a field sting had occurred and the severity of the reaction was compared to pretreatment reaction. RESULTS: Of 82 patients that were identified, 26 experienced a minimum of one adverse event. No deaths or severe anaphylactic reactions were reported. The most common adverse event was gastrointestinal upset. The overall reaction rate per injection was 2.8%. Only variation in sensitisation level (the minimum concentration of venom which elicited a positive intradermal reaction) was significantly different between groups (P = 0.014). Forty-one field challenges in 26 patients were documented. Therapy reduced the severity of reactions in 87.8% of challenges. No deaths were reported. CONCLUSION: Venom immunotherapy appears to be a safe and efficacious treatment for prevention of anaphylaxis due to insect stings in canine patients.

Reproductive resilience but not root architecture underpins yield improvement under drought in maize.

Because plants capture water and nutrients through roots, it was proposed that changes in root systems architecture (RSA) might underpin the 3-fold increase in maize (Zea mays L.) grain yield over the last century. Here we show that both RSA and yield have changed with decades of maize breeding, but not the crop water uptake. Results from X-ray phenotyping in controlled environments showed that single cross (SX) hybrids have smaller root systems than double cross (DX) hybrids for root diameters between 2465 µm and 181µm (P<0.05). Soil water extraction measured under field conditions ranged between 2.6 mm d-1 and 2.9 mm d-1 but were not significantly different between SX and DX hybrids. Yield and yield components were higher for SX than DX hybrids across densities and irrigation (P<0.001). Taken together, the results suggest that changes in RSA were not the cause of increased water uptake but an adaptation to high-density stands used in modern agriculture. This adaptation may have contributed to shift in resource allocation to the ear and indirectly improved reproductive resilience. Advances in root physiology and phenotyping can create opportunities to maintain long-term genetic gain in maize, but a shift from ideotype to crop and production system thinking will be required.

Effects of Dietary Resistant Starch on the Wnt Signaling Pathway and Preneoplastic Cells in the Colons of Azoxymethane-Treated Rats.

Dietary resistant starch (RS) has been suggested to reduce colonic neoplasia. To determine the effects of digestion-resistant cornstarch on colonic carcinogenesis and Wnt signaling in azoxymethane (AOM)-treated F344 rats, diets containing naturally occurring RS from corn lines derived partially from Guat209 (GUAT), AR16035 (AR), or a hybrid (ARxGUAT), containing 34.5 ± 2.0, 0.2 ± 0.1, and 1.9 ± 0.1% RS, respectively, were fed at 55% of the diet. GUAT-fed rats had increased cecal content and tissue weight and decreased cecal pH compared with AR- or ARxGUAT-fed rats. Numbers of aberrant crypt foci (ACF) were not different among diet groups. Increased numbers of crypts/focus were observed in AOM-injected rats fed GUAT compared with rats fed other diets. ß-catenin mRNA expression of the crypts was significantly increased in GUAT-fed rats injected with AOM relative to those injected with saline. These findings suggest that selected dietary RSs may at some level further enhance colonocyte proliferation and differentiation in an AOM-treated colon.

Effects of Enhancing School-Based Body Mass Index Screening Reports with Parent Education on Report Utility and Parental Intent To Modify Obesity Risk Factors.

BACKGROUND: School-based body mass index screenings (SBMIS) have been controversial. We aimed to determine if parents would indicate improved utility with SBMIS when the report included parent education and whether parental intent to modify obesity risk factors would vary with report type or child weight. METHODS: A cluster-controlled trial was conducted with 31 elementary schools randomized to distribute a standard SBMIS report or the standard report plus education (SBMIS+). A random subsample of parents completed a mailed survey (731 SBMIS, 738 SBMIS+). Using a two-stage cluster sampling design, logistic regression models with school-level random effect were used to assess differences between conditions and by weight category. RESULTS: Parents in the SBMIS+ condition vs. the standard condition were more likely to indicate that the report provided useful information (not significant) and an intent to help their child get enough sleep (p < 0.001). Parents of children who were overweight or obese were less likely than parents of children who were not to indicate that the report provided useful information about their child's weight status (p < 0.001) or access to resources (p < 0.05). However, these parents were more likely to plan a visit to healthcare provider (p < 0.001) and to intend to limit sugar-sweetened beverages (p < 0.05). CONCLUSIONS: Parental education can enhance the utility of the SBMIS report and parental intention to modify at least one obesity risk factor. SBMIS reports prompted parents of children with overweight and obesity to seek clinical care and limit sugar-sweetened drinks.

Effect of Dietary-Resistant Starch on Inhibition of Colonic Preneoplasia and Wnt Signaling in Azoxymethane-Induced Rodent Models.

Dietary fiber has been reported to prevent preneoplastic colon lesions. The aim of this study was to determine the effect of resistant starches, novel dietary fibers, on the development of colonic preneoplasia and Wnt signaling in azoxymethane (AOM)-treated rats and mice fed resistant starches at 55% of the diet after AOM treatment. Another objective was to determine the effect of resistant starches on the development of preneoplasia in rats treated with antibiotics (Ab), administered between AOM treatment and resistant starch feeding. Diets containing resistant starches, high-amylose (HA7), high-amylose-octenyl succinic anhydride (OS-HA7), or high-amylose-stearic acid (SA-HA7) were compared with control cornstarch (CS). The resistant starch content of the diets did not alter the yield of colonic lesions but animals treated with AOM and fed the diet with the highest resistant starch content, SA-HA7 developed the highest average aberrant crypt foci (ACF) per animal. Mice fed the OS-HA7 diet had decreased expression of some upstream Wnt genes in the colonic crypts. This study suggests that further research is needed to determine if resistant starch impacts colon carcinogenesis in rodents.