Albumin-ruthenium catalyst conjugate for bio-orthogonal uncaging of alloc group.

The employment of antibodies as a targeted drug delivery vehicle has proven successful which is exemplified by the emergence of antibody-drug conjugates (ADCs). However, ADCs are not without their shortcomings. Improvements may be made to the ADC platform by decoupling the cytotoxic drug from the delivery vehicle and conjugating an organometallic catalyst in its place. The resulting protein-metal catalyst conjugate was designed to uncage the masked cytotoxin administered as a separate entity. Macropinocytosis of albumin by cancerous cells suggests the potential of albumin acting as the tumor-targeting delivery vehicle. Herein reported are the first preparation and demonstration of ruthenium catalysts with cyclopentadienyl and quinoline-based ligands conjugated to albumin. The effective uncaging abilities were demonstrated on allyloxy carbamate (alloc)-protected rhodamine 110 and doxorubicin, providing a promising catalytic scaffold for the advancement of selective drug delivery methods in the future.

Disparate potential for readmission prevention exists among inpatient and outpatient procedures in a minimally invasive surgery practice.

BACKGROUND: Administrators have focused on decreasing postoperative readmissions for cost reduction without fully understanding their preventability. This study describes the development and implementation of a surgeon-led readmission review process that assessed preventability. METHODS: A gastrointestinal surgical group at a tertiary referral hospital developed and implemented a template to analyze inpatient and outpatient readmissions. Monthly stakeholder assessments reviewed and categorized readmissions as potentially preventable or not preventable. Continuous variables were examined by the Student's t test and reported as means and standard deviations. Categorical variables were examined by the Pearson χ2 statistic and Fisher's exact test. RESULTS: There were 61 readmission events after 849 inpatient operations (7.2%) and 16 after 856 outpatient operations (1.9%), the latter of which were all classified as potentially preventable. Colorectal procedures represented 65.6% of readmissions despite being only 37.2% of all cases. The majority (67.2%) of readmission events were not preventable. Compared to the not-preventable group, the potentially preventable group experienced more dehydration (30.0% vs 9.8%, P = .045) and ileostomy creation (78.6% vs 33.3%, P = .017). The potential for outpatient management to prevent readmission was significantly higher in the potentially preventable group (40.0% vs 0.0%, P < .001), as was premature discharge prevention (35.0% vs 0.0%, P < .001). CONCLUSION: The use of the standardized template developed for analyzing readmission events after inpatient and outpatient procedures identified a disparate potential for readmission prevention. This finding suggests that a singular focus on readmission reduction is misguided, with further work needed to evaluate and implement appropriate quality-based strategies.

Fluorinated Ethylamines as Electrospray-Compatible Neutral pH Buffers for Native Mass Spectrometry.

Native electrospray ionization mass spectrometry (ESI-MS) has emerged as a potent tool for examining the native-like structures of macromolecular complexes. Despite its utility, the predominant "buffer" used, ammonium acetate (AmAc) with pKa values of 4.75 for acetic acid and 9.25 for ammonium, provides very little buffering capacity within the physiological pH range of 7.0-7.4. ESI-induced redox reactions alter the pH of the liquid within the ESI capillary. This can result in protein unfolding or weakening of pH-sensitive interactions. Consequently, the discovery of volatile, ESI-compatible buffers, capable of effectively maintaining pH within a physiological range, is of high importance. Here, we demonstrate that 2,2-difluoroethylamine (DFEA) and 2,2,2-trifluoroethylamine (TFEA) offer buffering capacity at physiological pH where AmAc falls short, with pKa values of 7.2 and 5.5 for the conjugate acids of DFEA and TFEA, respectively. Native ESI-MS experiments on model proteins cytochrome c and myoglobin electrosprayed with DFEA and TFEA demonstrated the preservation of noncovalent protein-ligand complexes in the gas phase. Protein stability assays and collision-induced unfolding experiments further showed that neither DFEA nor TFEA destabilized model proteins in solution or in the gas phase. Finally, we demonstrate that multisubunit protein complexes such as alcohol dehydrogenase and concanavalin A can be studied in the presence of DFEA or TFEA using native ESI-MS. Our findings establish DFEA and TFEA as new ESI-compatible neutral pH buffers that promise to bolster the use of native ESI-MS for the analysis of macromolecular complexes, particularly those sensitive to pH fluctuations.

Continuous Ligand-Free Catalysis Using a Hybrid Polymer Network Support.

Although the pharmaceutical and fine chemical industries primarily utilize batch homogeneous reactions to carry out chemical transformations, emerging platforms seek to improve existing shortcomings by designing effective heterogeneous catalysis systems in continuous flow reactors. In this work, we present a versatile network-supported palladium (Pd) catalyst using a hybrid polymer of poly(methylvinylether-alt-maleic anhydride) and branched polyethyleneimine for intensified continuous flow synthesis of complex organic compounds via heterogeneous Suzuki-Miyaura cross-coupling and nitroarene hydrogenation reactions. The hydrophilicity of the hybrid polymer network facilitates the reagent mass transfer throughout the bulk of the catalyst particles. Through rapid automated exploration of the continuous and discrete parameters, as well as substrate scope screening, we identified optimal hybrid network-supported Pd catalyst composition and process parameters for Suzuki-Miyaura cross-coupling reactions of aryl bromides with steady-state yields up to 92% with a nominal residence time of 20 min. The developed heterogeneous catalytic system exhibits high activity and mechanical stability with no detectable Pd leaching at reaction temperatures up to 95 °C. Additionally, the versatility of the hybrid network-supported Pd catalyst is demonstrated by successfully performing continuous nitroarene hydrogenation with short residence times (<5 min) at room temperature. Room temperature hydrogenation yields of >99% were achieved in under 2 min nominal residence times with no leaching and catalyst deactivation for more than 20 h continuous time on stream. This catalytic system shows its industrial utility with significantly improved reaction yields of challenging substrates and its utility of environmentally-friendly solvent mixtures, high reusability, scalable and cost-effective synthesis, and multi-reaction successes.

Open preperitoneal ventral hernia repair: Prospective observational study of quality improvement outcomes over 18 years and 1,842 patients.

BACKGROUND: This study aimed to describe progressive evidence-based changes in perioperative management of open preperitoneal ventral hernia repair and subsequent surgical outcomes and to analyze factors that affect recurrence and wound complications. METHODS: Prospective, tertiary hernia center data (2004-2021) were examined for patients undergoing midline open preperitoneal ventral hernia repair with mesh. "Early" (2004-2012) and "Recent" (2013-2021) groups were based on surgery date. RESULTS: Comparison of Early (n = 675) versus Recent (n = 1,167) groups showed that Recent patients were, on average, older (56.9 ± 12.6 vs 58.7 ± 12.1 years; P < .001) with a lower body mass index (33.5 ± 8.3 vs 32.0 ± 6.8 kg/m2; P = .003) and a higher number of comorbidities (3.6 ± 2.2 vs 5.2 ± 2.6; P < .001). Recent patients had higher proportions of prior failed ventral hernia repair (46.5% vs 60.8%; P < .001), larger hernia defects (199.7 ± 232.8 vs 214.4 ± 170.5 cm2; P < .001), more Center for Disease Control class 3 or 4 wounds (11.3% vs 18.6%; P < .001), and more component separations (22.5% vs 45.7%; P < .001). Hernia recurrence decreased over time (7.1% vs 2.4%; P < .001), as did wound complication rates (26.7% vs 13.2%; P < .001). Comparing respective multivariable analyses (Early versus Recent), wound complications were associated with panniculectomy (odds ratio [95% confidence interval]: 2.9 [1.9-4.5], P < .001 vs 2.1 [1.4-3.3], P < .01), contaminated wounds (2.1 [1.1-3.7], P = .02 vs 1.8 [1.1-3.1], P = .02), anterior component separation technique (1.8 [1.1-2.9], P = .02 vs 3.2[1.9-5.3], P < .01), and operative time (per minute: 1.01 [1.008-1.015], P < .01 vs 1.004 [1.001-1.007], P < .01). Diabetes (2.6 [1.7-4.0], P < .01) and tobacco (1.8 [1.1-2.9], P = .02) were only significant in the early group. In both groups, recurrence was associated with wound complication (8.9 [4.1-20.1], P < .01 vs 3.4 [1.3-8.2]. P < .01) and recurrent hernias (4.9 [2.3-11.5], P < .01 vs 2.1 [1.1-4.2], P = .036). CONCLUSION: Despite significant increased patient complexity over time, detecting and implementing best practices as determined by recurring data analysis of a center's outcomes has significantly improved patient care results.

Anticancer Agents Derived from Cyclic Thiosulfonates: Structure-Reactivity and Structure-Activity Relationships.

Reported are structure-property-function relationships associated with a class of cyclic thiosulfonate molecules-disulfide-bond disrupting agents (DDAs)-with the ability to downregulate the Epidermal Growth Factor Receptor (HER) family in parallel and selectively induce apoptosis of EGFR+ or HER2+ breast cancer cells. Recent findings have revealed that the DDA mechanism of action involves covalent binding to the thiol(ate) from the active site cysteine residue of members of the protein disulfide isomerase (PDI) family. Reported is how structural modifications to the pharmacophore can alter the anticancer activity of cyclic thiosulfonates by tuning the dynamics of thiol-thiosulfonate exchange reactions, and the studies reveal a correlation between the biological potency and thiol-reactivity. Specificity of the cyclic thiosulfonate ring-opening reaction by a nucleophilic attack can be modulated by substituent addition to a parent scaffold. Lead compound optimization efforts are also reported, and have resulted in a considerable decrease of the IC50 /IC90 values toward HER-family overexpressing breast cancer cells.

Inhibitors of ERp44, PDIA1, and AGR2 induce disulfide-mediated oligomerization of Death Receptors 4 and 5 and cancer cell death.

Breast cancer mortality remains unacceptably high, indicating a need for safer and more effective therapeutic agents. Disulfide bond Disrupting Agents (DDAs) were previously identified as a novel class of anticancer compounds that selectively kill cancers that overexpress the Epidermal Growth Factor Receptor (EGFR) or its family member HER2. DDAs kill EGFR+ and HER2+ cancer cells via the parallel downregulation of EGFR, HER2, and HER3 and activation/oligomerization of Death Receptors 4 and 5 (DR4/5). However, the mechanisms by which DDAs mediate these effects are unknown. Affinity purification analyses employing biotinylated-DDAs reveal that the Protein Disulfide Isomerase (PDI) family members AGR2, PDIA1, and ERp44 are DDA target proteins. Further analyses demonstrate that shRNA-mediated knockdown of AGR2 and ERp44, or expression of ERp44 mutants, enhance basal DR5 oligomerization. DDA treatment of breast cancer cells disrupts PDIA1 and ERp44 mixed disulfide bonds with their client proteins. Together, the results herein reveal DDAs as the first small molecule, active site inhibitors of AGR2 and ERp44, and demonstrate roles for AGR2 and ERp44 in regulating the activity, stability, and localization of DR4 and DR5, and activation of Caspase 8.

Nationwide increase in component separation without concomitant rise in readmissions: A nationwide readmissions database analysis.

BACKGROUND: The use of component separation technique (CST) in complex abdominal wall reconstruction (AWR) increases the rate of primary musculofascial closure but can be associated with increased wound complications, which may require readmission. This study examines 3-year trends in readmissions for patients undergoing AWR with or without CST. METHODS: The Nationwide Readmissions Database was queried for patients undergoing elective AWR from 2016-2018. CST, demographic characteristics, and 90-day complications and readmissions were determined. CST versus non-CST readmissions were compared, including matched subgroups. Standard statistics and logistic regression were used. RESULTS: Over the 3-year period, 94,784 patients underwent AWR. There was an annual increase in the prevalence of CST: 4.0% in 2016; 6.1% in 2017; 6.7% in 2018 (P < .01), which is a 67.5% upsurge during that time. Most cases (82.3%) occurred at urban teaching hospitals, which had more comorbid patients (P < .01). The yearly 90-day readmission rate did not change: 16.0%, 18.2%, and 16.9% (P = .26). Readmissions were higher for CST patients than non-CST patients (17.1% vs 15.7%), but not in the matched subgroup (17.0% vs 16.4%; P = .41). Most commonly, readmissions were for infection (28.3%); 14.3% of readmitted patients underwent reoperation. Smoking, morbid obesity, diabetes, chronic lung disease, urban-teaching hospital status, and increased length of stay increased the chance of readmission (all P < .05). CONCLUSION: From 2016 to 2018, the use of CST increased 67.5% nationwide without an increase in readmissions. As we look toward clinical targets to reduce risk of readmission, modifiable health conditions, such as smoking, morbid obesity, and diabetes should be targeted during the prehabilitation process.

Complicated Diverticular Disease.

The modern management of colonic diverticular disease involves grouping patients into uncomplicated or complicated diverticulitis, after which the correct treatment paradigm is instituted. Recent controversies suggest overlap in management strategies between these two groups. While most reports still support surgical intervention for the treatment of complicated diverticular disease, more data are forthcoming suggesting complicated diverticulitis does not merit surgical resection in all scenarios. Given the significant risk for complication in surgery for diverticulitis, careful attention should be paid to patient and procedure selection. Here, we define complicated diverticulitis, discuss options for surgical intervention, and explain strategies for avoiding operative pitfalls that result in early and late postoperative complications.

Impact of Multidisciplinary Audit of Enhanced Recovery After Surgery (ERAS)® Programs at a Single Institution.

BACKGROUND: As Enhanced Recovery After Surgery (ERAS®) programs expand across numerous subspecialties, growth and sustainability on a system level becomes increasingly important and may benefit from reporting multidisciplinary and financial data. However, the literature on multidisciplinary outcome analysis in ERAS is sparse. This study aims to demonstrate the impact of multidisciplinary ERAS auditing in a hospital system. Additionally, we describe developing a financial metric for use in gaining support for system-wide ERAS adoption and sustainability. METHODS: Data from HPB, colorectal and urology ERAS programs at a single institution were analyzed from a prospective ERAS Interactive Audit System (EIAS) database from September 2015 to June 2019. Clinical 30-day outcomes for the ERAS cohort (n = 1374) were compared to the EIAS pre-ERAS control (n = 311). Association between improved ERAS compliance and improved outcomes were also assessed for the ERAS cohort. The potential multidisciplinary financial impact was estimated from hospital bed charges. RESULTS: Multidisciplinary auditing demonstrated a significant reduction in postoperative length of stay (LOS) (1.5 days, p < 0.001) for ERAS patients in aggregate and improved ERAS compliance was associated with reduced LOS (coefficient - 0.04, p = 0.004). Improved ERAS compliance in aggregate also significantly associated with improved 30-day survival (odds ratio 1.04, p = 0.001). Multidisciplinary analysis also demonstrated a potential financial impact of 44% savings (p < 0.001) by reducing hospital bed charges across all specialties. CONCLUSIONS: Multidisciplinary auditing of ERAS programs may improve ERAS program support and expansion. Analysis across subspecialties demonstrated associations between improved ERAS compliance and postoperative LOS as well as 30-day survival, and further suggested a substantial combined financial impact.

Repurposing Tranexamic Acid as an Anticancer Agent.

Tranexamic Acid (TA) is a clinically used antifibrinolytic agent that acts as a Lys mimetic to block binding of Plasminogen with Plasminogen activators, preventing conversion of Plasminogen to its proteolytically activated form, Plasmin. Previous studies suggested that TA may exhibit anticancer activity by blockade of extracellular Plasmin formation. Plasmin-mediated cleavage of the CDCP1 protein may increase its oncogenic functions through several downstream pathways. Results presented herein demonstrate that TA blocks Plasmin-mediated excision of the extracellular domain of the oncoprotein CDCP1. In vitro studies indicate that TA reduces the viability of a broad array of human and murine cancer cell lines, and breast tumor growth studies demonstrate that TA reduces cancer growth in vivo. Based on the ability of TA to mimic Lys and Arg, we hypothesized that TA may perturb multiple processes that involve Lys/Arg-rich protein sequences, and that TA may alter intracellular signaling pathways in addition to blocking extracellular Plasmin production. Indeed, TA-mediated suppression of tumor cell viability is associated with multiple biochemical actions, including inhibition of protein synthesis, reduced activating phosphorylation of STAT3 and S6K1, decreased expression of the MYC oncoprotein, and suppression of Lys acetylation. Further, TA inhibited uptake of Lys and Arg by cancer cells. These findings suggest that TA or TA analogs may serve as lead compounds and inspire the production of new classes of anticancer agents that function by mimicking Lys and Arg.

Recurrent incisional hernia repairs at a tertiary hernia center: Are outcomes really inferior to initial repairs?

BACKGROUND: Recurrent ventral hernia repairs are reported to have higher recurrence and complication rates than initial ventral hernia repairs. This is the largest analysis of outcomes for initial versus recurrent open ventral hernia repairs reported in the literature. METHODS: A prospective, institutional database at a tertiary hernia center was queried for patients undergoing open ventral hernia repairs with complete fascial closure and synthetic mesh placement. RESULTS: A total of 1,694 open ventral hernia repairs patients were identified, including 896 (52.9%) initial ventral hernia repairs and 798 (47.1%)recurrent ventral hernia repairs. Recurrent ventral hernia repair patients were more complex: older (P = .003), higher body mass index (P < .001), higher American Society of Anesthesiologists class (P < .001), incidence of diabetics (P = .003), comorbidities (P < .001), and larger hernia defects (133.3 ± 171.9 vs 220.2 ± 210.0; P < .001). Recurrent ventral hernia repairs also had longer operative times (161.6 ± 82.4 vs 188.2 ± 68.9 minutes; P < .001), increased use of preoperative botulinum toxin A injection (4.3% vs 10.1%; P = .01), components separation (19.2% vs 39.5%; P < .001), and panniculectomy (20.3% vs 35.8%; P < .001). The overall hernia recurrence rate was 4.4% at a mean follow-up of 36.6 ± 45.5 months. Between the initial ventral hernia repairs and recurrent ventral hernia repairs, the hernia recurrence rates were equivalent (4.2% vs 4.7%, P = .63). Rates of wound infection, seromas, hematomas, mesh infections, and wound related reoperations (P > .05) were nonsignificant. CONCLUSION: At a tertiary hernia center, despite higher-risk patients, larger hernia defects, and increased components separation in recurrent ventral hernia repairs, early recurrence rates, wound complications, and reoperations are similar to initial ventral hernia repairs.