Bauer Research Foundation

Platinum-based chemotherapeutics remain the standard of care for many solid tumors; however, they have dose-limiting toxicities. Silver(I) N-heterocyclic carbene complexes represent a novel class of metallodrugs with potential anticancer activity and improved tolerability. This study evaluated SCC5, a silver(I) acetate complex derived from 1,3-dimethyl-4,5-dichloroimidazole-2-ylidene, across a panel of human cancer cell lines and in vivo toxicity models. Mechanistic analysis of apoptosis was also performed using caspase-8 immunoblotting. Eight human cancer cell lines (melanoma, colon, renal, bladder, ovarian, and prostate) were treated with SCC5 and three FDA-approved platinum drugs (cisplatin, carboplatin, oxaliplatin). Antiproliferative activity was measured using the sulforhodamine B assay. In vivo toxicity was assessed in CD-1 mice receiving escalating intraperitoneal doses (10-50 mg/kg), with survival monitored over 21 days. Caspase-8 was analyzed by western blotting in SCC5-treated HT-29 cells. SCC5 exhibited half-maximal inhibitory doses ranging from 10 to 30 μM, comparable to carboplatin and was slightly less potent than cisplatin and oxaliplatin. However, SCC5 demonstrated superior safety, with 100% survival at doses that were lethal to platinum compounds, supporting its more favorable therapeutic index. Western blot analysis revealed dose- and time-dependent loss of caspase-8 expression following SCC5 treatment, suggesting activation of apoptosis-related pathways. SCC5 maintains broad-spectrum antiproliferative activity with markedly improved in vivo tolerability compared to platinum drugs. These findings support continued preclinical development of SCC5 as a novel silver-based chemotherapeutic.

Intrinsic factor (IF) is a glycoprotein crucial for cobalamin (vitamin B12) absorption in the human body. This study aimed to evaluate the binding affinity of nitrosylcobalamin (NO-Cbl), a cobalamin analog, to recombinant human IF derived from plants, using hydroxocobalamin (OH-Cbl) as a comparative standard. Surface plasmon resonance (SPR) was employed to assess the kinetic parameters of NO-Cbl and OH-Cbl interactions with plant- derived IF across various concentrations. SPR analysis demonstrated that NO-Cbl and OH-Cbl exhibited high binding affinities to IF, with equilibrium dissociation constant (KD) values in the picomolar range. OH-Cbl showed a slightly stronger binding affinity (KD = 4.79 × 10-11 M) than NO-Cbl (KD = 8.58 × 10-11 M). Despite NO-Cbl and OH-Cbl both being bound to IF, differences in binding affinity and stability were observed, particularly at higher concentrations. Variations in IF binding between NO-Cbl and OH-Cbl may be attributed to the saturation of binding sites or recognition issues specific to plant-derived IF. This study underscores the potential of NO-Cbl as a targeted therapeutic agent capable of leveraging natural cobalamin uptake pathways. These results also highlight the suitability of using recombinant plant-derived IF as a model for predicting the biological activity of cobalamin analogs despite the nuanced differences from native human IF.

ABSTRACT We hypothesize that managers anticipate a disproportionately larger price increase associated with rounded earnings per share (EPS) and make additional effort to round EPS when they plan to sell shares after the earnings announcement. Consistent with this hypothesis, we find that managers who round diluted EPS have higher managerial insider sales following the earnings announcement compared to managers who do not. Furthermore, we find that the positive association between rounding of diluted EPS and subsequent stock sales undertaken by chief financial officers (CFOs) is stronger when the level of abnormal stock repurchases is higher, consistent with managers’ strategic behavior.

We utilized inverse design to engineer the point-spread function (PSF) of a low-f-number, freeform diffractive microlens in an array, so as to enable extended depth of focus (DOF). Each square microlens of side 69 µm and focal length 40 µm (in a polymer film, n∼1.47) generated a square PSF of side ∼10 µm that was achromatic over the visible band (450 to 750 nm), and also exhibited an extended DOF of ∼ ± 2 µm. The microlens has a geometric f/# (focal length divided by aperture size) of 0.58 in the polymer material (0.39 in air). Since each microlens is a square, the microlens array (MLA) can achieve 100% fill factor. By placing this microlens array (MLA) directly on a high-resolution print, we demonstrated integral imaging with applications in physical security. The extended DOF preserves the optical effects even with expected film-thickness variations, thereby increasing robustness in practical applications. Since these multi-level diffractive MLAs are fabricated using UV-nanoimprint lithography, they have the potential for low-cost large volume manufacturing.

Instagram is not just a brand-marketing tool. This in-depth analysis highlights the power of Instagram storytelling tactics in driving conversions and website traffic for content marketers, exemplified by the successes of global media brands such as the Guardian and Vice. This article explains how both the Guardian and Vice reformat their on-site content offering for mobile to appeal to their Instagram audiences, and also publish episodic series to attract new and existing audiences into regularly ‘tuning in’ to their content in a bid to boost on-platform engagement and on-site traffic. From these strategies, the Guardian has grown 79 per cent in Instagram followers in 12 months, while Vice’s Instagram Stories now sit at a 50 per cent retention rate. Additionally, this article emphasises the effectiveness of combining content strategies with social media strategies, and why it is imperative to be able to distinguish the differences between the two. The article also further educates content marketers on how to build-out a lucrative Instagram strategy and boost return on investment via data and analytics platforms, and campaign optimisation.

Online grocery shopping is becoming an integral part of life for more and more customers around the world and has truly changed the way consumers acquire their groceries. Nevertheless, the offline environment is still a priority for most customers. Therefore, it is not surprising that new technologies are also being introduced in traditional stores. The purpose of this paper is to explore if all generations of customers equally perceive pressure to apply new technologies into the purchasing process and how previous online grocery shopping acceptance can influence customer behaviour. This research was conducted on a sample of 1,050 online respondents. The answers of respondents have a nominal character. Therefore, Pearson´s chi-square test was used for testing. Subsequently, the frequency analysis was used for a more detailed examination. The results indicate that online grocery shopping acceptance positively influences the perception of new technologies from the perspective of all generations of customers. An interesting finding is that if traditional retailers entered the online market, 67% of online grocery shoppers would change retailers. This paper brings a new perspective on online and offline generations of customers and states that online grocery shopping acceptance is a predictor of positive perception of other technologies in retailing. Managers should take steps to increase the acceptance of technologies in stores, which will facilitate the business processes in the store and optimize the use of the workforce. This paper also demonstrates an opportunity for traditional retailers to enter the online marketplace.

Objective- Gut microbiota-dependent metabolites, in particular trimethylamine N-oxide (TMAO), have recently been reported to promote atherosclerosis and thrombosis. Here, we examined for the first time the relation of TMAO and the risk of incident cardiovascular events in patients with recent first-ever ischemic stroke in 2 independent prospective cohorts. Moreover, the link between TMAO and proinflammatory monocytes as a potential contributing factor for cardiovascular risk in stroke patients was studied. Approach and Results- In a first study (n=78), higher TMAO plasma levels were linked with an increased risk of incident cardiovascular events including myocardial infarction, recurrent stroke, and cardiovascular death (fourth quartile versus first quartile; hazard ratio, 2.31; 95% CI, 1.25-4.23; P<0.01). In the second independent validation cohort (n=593), high TMAO levels again heralded marked increased risk of adverse cardiovascular events (fourth quartile versus first quartile; hazard ratio, 5.0; 95% CI, 1.7-14.8; P<0.01), and also after adjustments for cardiovascular risk factors including hypertension, diabetes mellitus, LDL (low-density lipoprotein) cholesterol, and estimated glomerular filtration rate (hazard ratio, 3.3; 95% CI, 1.2-10.9; P=0.04). A significant correlation was also found between TMAO levels and percentage of proinflammatory intermediate CD14++CD16+ monocytes ( r=0.70; P<0.01). Moreover, in mice fed a diet enriched with choline to increase TMAO synthesis, levels of proinflammatory murine Ly6Chigh monocytes were higher than in the chow-fed control group (choline: 9.2±0.5×103 per mL versus control: 6.5±0.5×103 per mL; P<0.01). This increase was abolished in mice with depleted gut microbiota (choline+antibiotics: 5.4±0.7×103 per mL; P<0.001 versus choline). Conclusions- The present study demonstrates for the first time a graded relation between TMAO levels and the risk of subsequent cardiovascular events in patients with recent prior ischemic stroke. Our data support the notion that TMAO-related increase of proinflammatory monocytes may add to elevated cardiovascular risk of patients with increased TMAO levels.