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BackgroundMinimally invasive (MIS) cholecystectomies have become standard due to patient and hospital advantages; however, this approach is not always achievable. Acute and gangrenous cholecystitis increase the likelihood of conversion from MIS to open cholecystectomy. This study aims to examine patient and hospital factors underlying differential utilization of MIS vs open cholecystectomies indicated for acute cholecystitis.MethodsThis is a retrospective, observational cohort study of patients with acute cholecystitis who underwent a cholecystectomy between 2016 and 2018 identified from the California Office of Statewide Health Planning and Development database. Univariate analysis and multivariable logistic regression models were used to analyze patient, geographic, and hospital variables as well as surgical approach.ResultsOur total cohort included 53,503 patients of which 98.4% (n = 52,673) underwent an initial minimally invasive approach and with a conversion rate of 3.3% (n = 1,759). On multivariable analysis advancing age increased the likelihood of either primary open (age 40 to

BACKGROUND: Pancreatic neuroendocrine tumors (pNETs) are genomically diverse tumors. The management of newly diagnosed well-differentiated pNETs is limited by a lack of sensitivity of existing biomarkers for prognostication. Our goal was to investigate the potential utility of genetic markers as a predictor of progression-free survival (PFS) and recurrence-free survival (RFS). METHODS: Whole-exome sequencing of resected well-differentiated, low and intermediate-grade (G1 and G2) pNETs and normal adjacent tissue from patients who underwent resection from 2005 to 2015 was performed. Genetic alterations were classified using pan-genomic and oncogenic pathway classifications. Additional samples with genetic and clinicopathologic data available were obtained from the publicly available International Cancer Genome Consortium (ICGC) database and included in the analysis. The prognostic relevance of these genomic signatures on PFS and RFS was analyzed. RESULTS: Thirty-one patients who underwent resection for pNET were identified. Genomic analysis of mutational, copy number, cytogenetic, and complex phenomena revealed similar patterns to prior studies of pNETs with relatively few somatic gene mutations but numerous instances of copy number changes. Analysis of genomic and clinicopathologic outcomes using the combined data from our study as well as the ICGC pNET cohort (n = 124 patients) revealed that the recurrent pattern of whole chromosome loss (RPCL) and metastatic disease were independently associated with disease progression. When evaluating patients with local disease at the time of resection, RPCL and alterations in the TGFβ oncogenic pathway were independently associated with the risk of recurrence. CONCLUSIONS: Well-differentiated pNETs are genomically diverse tumors. Pathway signatures may be prognostic for predicting disease progression and recurrence.

Drs. John and Ford reported in biomedicines that a variant transcript encoding receptor tyrosine kinase-like orphan receptor 1 (ROR1), namely ENST00000545203 or variant 3 (ROR1V3), was a predominant ROR1 transcript of neoplastic or normal cells in the Bioinformatic database, including GTEx and the 33 datasets from TCGA. Unlike the full-length ROR1 transcript, Drs. John and Ford deduced that ROR1V3 encoded a cytoplasmic ROR1 protein lacking an apparent signal peptide necessary for transport to the cell surface, which they presumed made it unlikely to function as a surface receptor for Wingless/Integrated (Wnt) factors. Moreover, they speculated that studies evaluating ROR1 via immunohistochemistry using any one of several anti-ROR1 mAbs actually may have detected cytoplasmic protein encoded by ROR1V3 and that anti-cancer therapies targeting surface ROR1 thus would be ineffective against “cytoplasmic ROR1-positive” cancers that express predominately ROR1V3. We generated lentivirus vectors driving the expression of full-length ROR1 or the ROR1v3 upstream of an internal ribosome entry site (IRES) of the gene encoding a red fluorescent reporter protein. Although we find that cells that express ROR1 have surface and cytoplasmic ROR1 protein, cells that express ROR1v3 neither have surface nor cytoplasmic ROR1, which is consistent with our finding that ROR1v3 lacks an in-frame initiation codon for ribosomal translation into protein. We conclude that the detection of ROR1 protein in various cancers cannot be ascribed to the expression of ROR1v3.

Abstract Chemoprevention is one of the accessible strategies for preventing, delaying or reversing cancer processing utilizing chemical intervention of carcinogenesis. NAD(P)H quinone oxidoreductase 1 (NQO1) is a xenobiotic metabolizing cytosolic enzyme/protein with important functional properties towards oxidation stress, supporting its ability in detoxification/chemoprotective role. A set of 3,5-diylidene-4-piperidones (as curcumin mimics) bearing alkyl sulfonyl group were synthesized with potential NQO1 induction properties. Compounds 5ab (R = 2-MeOC6H4, R’ = Me) and 5ac (R = 2-MeOC6H4, R’ = Et) are the most promising agents synthesized (% induction of NQO1 = 51.562, 45.793) relative to that of 4’-bromoflavone (4’-BF, reference standard) at 10 µM. LPS-induced iNOS production in RAW264.7 macrophages of the most promising agents discovered (5ab and 5ac) displayed concentration-dependent with comparable activities to the reference anti-inflammatory drug indomethacin. Molecular modeling studies (including QSAR, molecular docking and molecular dynamics) were accessed supporting the observed biological profiles.

Abstract: Children’s Oncology Group study AALL1931 investigated the efficacy and safety of recombinant Erwinia asparaginase (JZP458) in patients with acute lymphoblastic leukemia/lymphoblastic lymphoma and hypersensitivity reactions/silent inactivation to Escherichia coli–derived asparaginases. Each pegylated Escherichia coli asparaginase dose remaining in a patient’s treatment plan was replaced by intramuscular (IM) or IV JZP458 (6 doses) administered Monday/Wednesday/Friday (MWF). Three IM cohorts (1a [25 mg/m2 MWF], n = 33; 1b [37.5 mg/m2 MWF], n = 83; 1c [25/25/50 mg/m2 MWF], n = 51) and 1 IV cohort (25/25/50 mg/m2 MWF, n = 62) were evaluated. The proportion (95% confidence interval [CI]) of patients maintaining nadir serum asparaginase activity (NSAA) levels of ≥0.1 IU/mL at the last 72 (primary end point) and 48 hours during course 1 was 90% (95% CI, 81-98) and 96% (95% CI, 90-100) in IM cohort 1c, respectively, and 40% (95% CI, 26-54) and 90% (95% CI, 82-98) in the IV cohort. Population pharmacokinetic modeling results were comparable with observed data, predicting the vast majority of patients would maintain therapeutic NSAA levels when JZP458 is administered IM or IV 25 mg/m2 every 48 hours, or IM 25/25/50 mg/m2 MWF, or with mixed IM and IV administration (IV/IV/IM 25/25/50 mg/m2 MWF). Drug discontinuation occurred in 23% and 56% of patients in the IM and IV cohorts, respectively; 13% and 33% because of treatment-related adverse events (mainly allergic reactions and pancreatitis). JZP458 achieves therapeutic NSAA levels via multiple IM and IV dosing schedules based on combined observed and modeled data with a safety profile consistent with other asparaginases. This trial was registered at www.ClinicalTrials.gov as #NCT04145531.

Abstract Targeted therapy is preferable over other therapeutics due to its limitation of drawbacks and better pharmaceutical outcomes. VEGF and its receptors have been observed to be hyper-activated in many cancer types and are considered promising targets for assigning anticancer agents. The current study is directed towards synthesis of novel antiproliferative 2-oxoindolin-3-ylidenes incorporating urea function with VEGFR-2 properties. The targeted agents were obtained through a two-step reaction. Addition of the appropriate 1-(acetylphenyl)-3-phenylurea 9a,b to the corresponding isatin 10a–f in ethanol containing a quantitative amount of Et2NH followed by acidic dehydration (AcOH/HCl) afforded the targeted agents 12a–j. Promising antiproliferation properties (MTT assay) were observed for most of the synthesized agents against HCT116 (colon), MCF7 (breast) and PaCa2 (pancreatic) cancer cell lines relative to sunitinib. VEGFR-2 inhibitory properties are consistent with the antiproliferation properties exhibited against the tested cell lines. Compound 12b (R = 4-NHCONHPh, R′ = H; % inhibition = 87.2) is the most promising/potent anti-VEGFR-2 agent synthesized with activity close to that of sunitinib (% inhibition = 89.4) at 10 μM. Molecular docking studies (PDB: 3WZE and 3AGD) support the antiproliferation effects against cancer cell lines tested with VEGFR-2 inhibitory properties. The results are consistent with collaboration of the pharmacophores considered (2-oxoindolyl heterocycle and urea) in improving the bio-properties.

Among electromagnetic methods of short-term earthquake prediction, an approach is being actively developed based on the phenomenon of magnetic ultra-low-frequency (ULF) power depression occurring a few days before an earthquake. In particular, a nighttime geomagnetic power depression in the band 0.03–0.05 Hz was observed approximately 5 days before the catastrophic Tohoku 2011 earthquake. To verify the reliability of this method, we performed an extended analysis using data from magnetometer arrays JMA, MAGDAS, PWING, and INTERMAGNET. The selected stations included sites close to the epicenter (

The laws of the public office are based on occupying its positions and the public utilities are running on setting the conditions for experience, competence and good reputation, but this matter is not without the issuance of actions from the employee requiring the administration to take the appropriate action to correct the error in job behavior, which results in withdrawing the hand until the truth emerges and this procedure may be By the rule of law, or it may be a use of the discretionary power of the administration at other times, which must be based on foundations that prevent the administration’s abuse of its authority and guarantee the public interest and the interest of the investigation, so withdrawing the hand means that the employee is cut off from permanence and is prevented from being in his department for a certain period, and it is not a penalty. Discipline,

Background: Children and adolescents with intellectual disabilities commonly experience emotion regulation difficulties. To better understand emotion regulation in this population, the views of their teachers were considered. Methods: Twenty-nine teachers participated in two focus groups. This study utilized qualitative methods to determine if the emotion regulation experiences of this population, as perceived by their teachers, map onto the five domains of the process model of emotion regulation: situation selection, situation modification, attentional deployment, cognitive change, and response modulation. Results: A thematic analysis indicated the data from both focus groups was consistent and mapped onto the five domains of the process model; with several additional themes and sub-themes identified. Conclusions: Perspectives provided by teachers affirmed that the process model of emotion regulation is relevant to children and adolescents with intellectual disabilities. Future research might consider developing the themes identified in this qualitative study into quantitative questionnaire items and validating that measure.

Receptor tyrosine kinase-like orphan receptor 1 (ROR1) is an oncoembryonic surface antigen expressed on the neoplastic cells of patients with chronic lymphocytic leukemia (CLL) or other types of cancer, but not on virtually all normal postpartum tissues (Fukuda T., et al., PNAS, 105:3047, 2008). Zilovertamab (also known as UC-961 or cirmtuzumab) is a humanized anti-ROR1 monoclonal antibody (mAb) currently under clinical investigation; this mAb is capable of blocking ROR1-signaling, which can contribute to cancer-cell migration, proliferation, survival, and self-renewal. We generated a glycoengineered form of zilovertamab (GE- zilovertamab) and examined whether it could mediate enhanced antibody-dependent cellular cytotoxicity (ADCC) against neoplastic cells that express ROR1. Initial studies used Jurkat-Lucia™ NFAT-CD16 cells (Invivogen, San Diego, CA, USA) which express high-affinity CD16A (FcγRIIIA, V158 allotype) as effector cells (EC), and the CLL-cell line MEC1, or MEC1 cells transduced to express ROR1 (MEC1-ROR1), as target cells (TC), which each also express CD20. Co-culture of Jurkat-Lucia cells for 6 hours with the anti-CD20 mAb rituximab and MEC1 or MEC1-ROR1 cells induced Jurkat-Lucia cells to express a luciferase reporter gene under the control of an ISG54 minimal promoter fused to six NFAT response elements; this endowed the Jurkat-Lucia cells with high luminescence activity that was not observed in co-cultures of EC and TC without added mAb. Neither zilovertamab nor GE-zilovertamab endowed Jurkat-Lucia cells with higher than background luminescence activity when co-cultured with MEC1 cells. However, GE-zilovertamab could induce high levels of luminescence activity in Jurkat-Lucia cells co-cultured with MEC1-ROR1 cells that was comparable to that of rituximab, and significantly greater than that of zilovertamab. We generated an orthogonal system with which to examine the relative ADCC activity of each of these mAb, using EC generated from the NK cell line, NK92, which we transduced with a lentivirus encoding a newly-generated high-affinity variant of CD16A (CD16v), which has been modified to block its cleavage by ADAM17. NK92 or NK92-CD16v were used as EC to effect cytolysis of Cr 51-labeled MEC1, MEC1-ROR1, or primary CLL cells in a chromium-release assay. Addition of rituximab to co-cultures of EC with Cr 51-labeled MEC1, MEC1-ROR1, or primary CLL caused mAb-dose-dependent ADCC of each of these TC by NK92-CD16v that was significantly greater than that by parental NK92 cells. Again, neither zilovertamab nor GE-zilovertamab could direct ADCC by NK92-CD16v or NK92 ADCC of MEC1 cells, which lack ROR1. However, GE-zilovertamab directed dose-dependent ADCC of MEC1-ROR1 or primary ROR1 + CLL cells by either NK92-CD16v or NK92 at levels comparable to that directed by rituximab for either EC population; such levels were significantly greater than that directed by zilovertamab. ROR1 + CLL cells harboring del(17p) or mutations in TP53 (del(17p)/m TP53) and/or that were resistant to targeted therapies (e.g., inhibitors of BTK or BCL2), were as susceptible to GE-zilovertamab-directed ADCC as were CLL cells without del(17p)/m TP53 from patients who had not had prior therapy. These data demonstrate that GE-zilovertamab can direct high-level ADCC lysis of ROR1-expressing neoplastic cells with greater activity than zilovertamab, encouraging development of clinical studies to evaluate GE-zilovertamab for therapy of patients with CLL or other ROR1-positive cancers.

BACKGROUND: Duodenal neuroendocrine tumors (dNETs) are rare, and their management is not well-defined. National Comprehensive Cancer Network (NCCN) guidelines recommend surgical resection of large dNETs (> 2 cm) and endoscopic resection of small tumors ( 3 cm. Kaplan-Meier and multivariable Cox proportional hazards models were used for survival analysis. RESULTS: The study included 465 patients, with 124 (26.7%) undergoing surgical resection. The average age was 61.9 years, and tumor sizes ranged from 0.1 to 10.5 cm. Endoscopic resection had 40.5% of tumors between 0 and 0.5 cm, while surgery had only 21% (p

BACKGROUND: Obesity is a major threat to public health and traditional bariatric surgery continues to have low utilization. Endoscopic treatments for obesity have emerged that offer less risk, but questions remain regarding efficacy, durability, and safety. We compared the efficacy of endoscopic bariatric procedures as compared to other existing treatments. METHODS: A literature search of Embase, Cochrane Central, and Pubmed was conducted from January 1, 2014 to December 7, 2021, including endoscopic bariatric therapies that were FDA or CE approved at the time of search to non-endoscopic treatments. Thirty-seven studies involving 15,639 patients were included. Primary outcomes included % total body weight loss (%TBWL), % excess body weight loss (%EBWL), and adverse events. Secondary outcomes included quality of life data and differences in hemoglobin A1C levels. Strength of clinical trial and observational data were graded according to the Cochrane methods. RESULTS: Intragastric balloons achieved greater %TBWL with a range of 7.6-14.1% compared to 3.3-6.7% with lifestyle modification at 6 months, and 7.5-14.0% compared to 3.1-7.9%, respectively, at 12 months. When endoscopic sleeve gastroplasty (ESG) was compared to laparoscopic sleeve gastrectomy (LSG), ESG had less %TBWL at 4.7-14.4% compared to 18.8-26.5% after LSG at 6 months, and 4.5-18.6% as compared to 28.4-29.3%, respectively, at 12 months. For the AspireAssist, there was greater %TBWL with aspiration therapy compared to lifestyle modification at 12 months, 12.1-18.3% TBWL versus 3.5-5.9% TBWL, respectively. All endoscopic interventions had higher adverse events rates compared to lifestyle modification. CONCLUSION: This review is the first to evaluate various endoscopic bariatric therapies using only RCTs and observational studies for evaluation of weight loss compared with conservative management, lifestyle modification, and bariatric surgery. Endoscopic therapies result in greater weight loss compared to lifestyle modification, but not as much as bariatric surgery. Endoscopic therapies may be beneficial as an alternative to bariatric surgery.

BACKGROUND: Antiplatelet agents are central in the management of vascular disease. The use of dual antiplatelet therapy (DAPT) for the management of thromboembolic complications must be weighed against bleeding risk in the perioperative setting. This balance is critical in patients undergoing cardiac or non-cardiac surgery. The management of patients on DAPT for any indication (including stents) is not clear and there is limited evidence to guide decision-making. This review summarizes current evidence since 2015 regarding the occurrence of major adverse events associated with continuing, suspending, or varying DAPT in the perioperative period. METHODS: A research librarian searched PubMed and Cochrane from November 30, 2015 to May 17, 2022, for relevant terms regarding adult patients on DAPT for any reason undergoing surgery, with a perioperative variation in DAPT strategy. Outcomes of interest included the occurrence of major adverse cardiac events, major adverse limb events, all-cause death, major bleeding, and reoperation. We considered withdrawal or discontinuation of DAPT as stopping either aspirin or a P2Y12 inhibitor or both agents; continuation of DAPT indicates that both drugs were given in the specified timeframe. RESULTS: Eighteen observational studies met the inclusion criteria. No RCTs were identified, and no studies were judged to be at low risk of bias. Twelve studies reported on CABG. Withholding DAPT therapy for more than 2 days was associated with less blood loss and a slight trend favoring less transfusion and surgical re-exploration. Among five observational CABG studies, there were no statistically significant differences in patient death across DAPT management strategies. Few studies reported cardiac outcomes. The remaining studies, which were about procedures other than exclusively CABG, demonstrated mixed findings with respect to DAPT strategy, bleeding, and ischemic outcomes. CONCLUSION: The evidence base on the benefits and risks of different perioperative DAPT strategies for patients with stents is extremely limited. The strongest signal, which was still judged as low certainty evidence, is that suspension of DAPT for greater than 2 days prior to CABG surgery is associated with less bleeding, transfusions, and re-explorations. Different DAPT strategies association with other outcomes of interest, such as MACE, remains uncertain. SYSTEMATIC REVIEW REGISTRATION: A preregistered protocol for this review can be found on the PROSPERO International Prospective Register of systematic reviews ( http://www.crd.york.ac.uk/PROSPERO/ ; registration number: CRD42022371032).

BACKGROUND: Whether laparoscopic approach to gastrectomy for gastric cancer (GC) reduces the risk of pneumonia remains unknown. In this study, we compared pneumonia outcomes for patients with GC who underwent either laparoscopic gastrectomy (LG) or open gastrectomy (OG). METHODS: The ACS NSQIP database was queried to identify patients with GC who underwent LG or OG between Jan 2012 - Dec 2018. Outcomes were compared using regression models. A post-hoc analysis was performed for elderly patients. RESULTS: The study cohort included 2661 patients, 23.4 % undergoing LG. Laparoscopic approach lowered pneumonia risk (OR 0.47, p = .028) and reduced hospital length of stay, (5.3 vs 7.1 days, p < .001). Elderly patients undergoing LG demonstrated similar benefits. Risk factors for pneumonia included advanced age, dyspnea and weight-loss, whereas laparoscopic approach reduced this risk. CONCLUSIONS: LG in patients with GC has both statistically and clinically significant advantages over OG with respect to pneumonia. Further studies are needed to validate the relationship between postoperative pneumonia and surgical approach for gastrectomy.

In response to concerns about healthcare access and long wait times within the Veterans Health Administration (VA), Congress passed the Choice Act of 2014 and the Maintaining Internal Systems and Strengthening Integrated Outside Networks (MISSION) Act of 2018 to create a program for patients to receive care in non-VA sites of care, paid by VA. Questions remain about the quality of surgical care between these sites in specific and between VA and non-VA care in general. This review synthesizes recent evidence comparing surgical care between VA and non-VA delivered care across the domains of quality and safety, access, patient experience, and comparative cost/efficiency (2015 to 2021). Eighteen studies met the inclusion criteria. Of 13 studies reporting quality and safety outcomes, 11 reported that quality and safety of VA surgical care were as good as or better than non-VA sites of care. Six studies of access did not have a preponderance of evidence favoring care in either setting. One study of patient experience reported VA care as about equal to non-VA care. All 4 studies of cost/efficiency outcomes favored non-VA care. Based on limited data, these findings suggest that expanding eligibility for veterans to get care in the community may not provide benefits in terms of increasing access to surgical procedures, will not result in better quality, and may result in worse quality of care, but may reduce inpatient length of stay and perhaps cost less.