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1.
JACC CardioOncol ; 6(3): 421-435, 2024 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-38983386

RESUMEN

Background: Modifiable cardiovascular risk factors constitute a significant cause of cardiovascular disease and mortality among patients with cancer. Recent studies suggest a potential link between neighborhood walkability and favorable cardiovascular risk factor profiles in the general population. Objectives: This study aimed to investigate whether neighborhood walkability is correlated with favorable cardiovascular risk factor profiles among patients with a history of cancer. Methods: We conducted a cross-sectional study using data from the Houston Methodist Learning Health System Outpatient Registry (2016-2022) comprising 1,171,768 adults aged 18 years and older. Neighborhood walkability was determined using the 2019 Walk Score and divided into 4 categories. Patients with a history of cancer were identified through International Classification of Diseases-10th Revision-Clinical Modification codes (C00-C96). We examined the prevalence and association between modifiable cardiovascular risk factors (hypertension, diabetes, smoking, dyslipidemia, and obesity) and neighborhood walkability categories in cancer patients. Results: The study included 121,109 patients with a history of cancer; 56.7% were female patients, and 68.8% were non-Hispanic Whites, with a mean age of 67.3 years. The prevalence of modifiable cardiovascular risk factors was lower among participants residing in the most walkable neighborhoods compared with those in the least walkable neighborhoods (76.7% and 86.0%, respectively). Patients with a history of cancer living in very walkable neighborhoods were 16% less likely to have any risk factor compared with car-dependent-all errands neighborhoods (adjusted OR: 0.84, 95% CI: 0.78-0.92). Sensitivity analyses considering the timing of events yielded similar results. Conclusions: Our findings demonstrate an association between neighborhood walkability and the burden of modifiable cardiovascular risk factors among patients with a medical history of cancer. Investments in walkable neighborhoods may present a viable opportunity for mitigating the growing burden of modifiable cardiovascular risk factors among patients with a history of cancer.

3.
Ann Surg Oncol ; 2024 Jun 01.
Artículo en Inglés | MEDLINE | ID: mdl-38824193

RESUMEN

BACKGROUND: Immunotherapy is emerging as a promising option for certain locally advanced and metastatic cutaneous malignancies. However, the role of neoadjuvant immunotherapy (NIO) in Merkel cell carcinoma (MCC) with clinically detected regional lymph node metastasis (CDRLNM) has not been fully elucidated. METHODS: For this study, MCC patients with CDRLNM who underwent surgical excision were selected from the National Cancer Database (NCDB). Those who received NIO were propensity-matched with those who did not, and Kaplan-Meier analysis was used to compare overall survival (OS). RESULTS: Of the 1809 selected patients, 356 (19.7%) received NIO followed by wide excision (n = 352, 98.9%) or amputation (n = 4, 1.1%). The rate of complete pathologic response for the primary tumor (ypT0) was 45.2%. Only 223 patents (63.4%) also underwent lymph node dissection (LND). The complete pathologic nodal response (ypN0) rate for these patients was 17.9%. A pathologic complete response of both the primary tumor and the nodal basin (ypT0 ypN0) was seen in 16 of the 223 patients who underwent both primary tumor surgery and LND. Subsequently, 151 pairs were matched between the NIO and no-NIO groups (including only patients with LND). Kaplan-Meier analysis demonstrated a significant OS improvement with NIO (median not reached vs. 35.0 ± 8.0 months; p = 0.025). The 5-year OS was 57% in the NIO group versus 44% in no-NIO group (p = 0.021). CONCLUSION: The study suggests that NIO in MCC with CDRLNM provides improved OS in addition to promising rates of primary complete response, which could change the profile of surgical resection. This supports ongoing clinical trials exploring the use of NIO in MCC.

4.
Ann Surg ; 2024 Jun 06.
Artículo en Inglés | MEDLINE | ID: mdl-38842190

RESUMEN

OBJECTIVE: We aim to quantify the rate of progression in surveilled cysts and assess what factors should indicate delayed resection. SUMMARY BACKGROUND DATA: Side-branch intraductal papillary mucinous neoplasms (SB-IPMNs) are increasingly discovered, making it challenging to identify which patients require resection, thus avoiding inappropriate treatment. Most incidental lesions are surveyed, yet the consequences of that decision remain uncertain. METHODS: A prospectively maintained database of pancreatic cystic neoplasms was queried for patients with SB-IPMN. Patients with ≥2 imaging studies >6 months apart were included. Clinically relevant progression (CR-Progression) was defined by symptoms, worrisome/high-risk stigmata, or invasive cancer (IC). Growth ≥5 mm in 2 years is considered CR-Progression; size ≥3 cm alone is not. RESULTS: Between 1997-2023,1,337 patients were diagnosed with SB-IPMN. Thirty-seven (2.7%) underwent up-front surgery; 1,000 (75.0%) had >6 months surveillance.The rate of CR-progression was 15.3% (n=153) based on size increase (n=63, 6.3%), main-duct involvement (n=48, 4.8%), symptoms (n=8, 5.0%), or other criteria (n=34, 3.4%). At a median follow-up of 6.6 years (IQR 3.0-10.26), 17 patients (1.7%) developed IC. Those with CR-progression developed IC in 11.1% (n=17) and high-grade dysplasia (HGD) in 6.5% (n=10). Nearly half of the cancers were not contiguous with the surveyed SB-IPMN.Size ≥3 cm was not associated with HGD/IC (P=0.232). HGD/IC was least common in CR-progression determined by size growth (6.3%) versus main-duct involvement (24%) or other (43%, P<0.001)Patients with CR-progression demonstrated improved survival (OS) with resection on time-to-event (P<0.001) and multivariate cox-regression (HR=0.205, 0.096-0.439, P<0.001) analyses. OS was not improved with resection in all patients (P=0.244). CONCLUSION: Clinically relevant progression for SB-IPMNs is uncommon with development of cancer anywhere in the pancreas being rare. Initial size should not drive resection. Long-term and consistent non-operative surveillance is warranted, with surgery currently reserved for CR-progression knowing that the majority of these still harbor low grade pathology.

5.
Surgeon ; 2024 Jun 10.
Artículo en Inglés | MEDLINE | ID: mdl-38862376

RESUMEN

INTRODUCTION: As hospitals strive to reduce their environmental footprint, there is an ongoing debate over the environmental implications of reusable versus disposable linens in operating rooms (ORs). This research aimed to compare the environmental impact of reusable versus single-use OR bed covers and lift sheets using life cycle assessment (LCA) methodology. METHODS: LCA is an established tool with rigorous methodology that uses science-based processes to measure environmental impact. This study compared the impacts of three independent system scenarios at a single large academic hospital: reusable bed covers with 50 laundry cycles and subsequent landfill disposal (System 1), single-use bed covers with waste landfill disposal (System 2), and single-use bed covers with waste disposal using incineration (System 3). RESULTS: The total carbon footprint of System 1 for 50 uses was 19.83 â€‹kg carbon dioxide equivalents (CO2-eq). System 2 generated 64.99 â€‹kg CO2-eq. For System 3, the total carbon footprint was 108.98 â€‹kg CO2-eq. The raw material extraction for all the material to produce an equivalent 50 single-use OR bed cover kits was tenfold more carbon-intensive than the reusable bed cover. Laundering one reusable OR bed cover 50 times was more carbon intensive (12.12 â€‹kg CO2-eq) than landfill disposal of 50 single-use OR bed covers (2.52 â€‹kg CO2-eq). DISCUSSION: Our analysis demonstrates that one reusable fabric-based OR bed cover laundered 50 times, despite the carbon and water-intensive laundering process, exhibits a markedly lower carbon footprint than its single-use counterparts. The net difference is 45.16 â€‹kg CO2-eq, equivalent to driving 115 miles in an average gasoline-powered passenger vehicle. This stark contrast underscores the efficacy of adopting reusable solutions to mitigate environmental impact within healthcare facilities.

6.
J Minim Invasive Surg ; 27(2): 95-108, 2024 Jun 15.
Artículo en Inglés | MEDLINE | ID: mdl-38887001

RESUMEN

Purpose: Postoperative pancreatic fistula (POPF) remains a devastating complication of pancreatoduodenectomy (PD). Minimally invasive PD (MIPD), including laparoscopic (LPD) and robotic (RPD) approaches, have comparable POPF rates to open PD (OPD). However, we hypothesize that the likelihood of having a more severe POPF, as defined as clinically relevant POPF (CR-POPF), would be higher in an MIPD relative to OPD. Methods: The American College of Surgeons National Surgical Quality Improvement Program (ACS NSQIP) targeted pancreatectomy dataset (2014-2020) was reviewed for any POPF after OPD. Propensity score matching (PSM) compared MIPD to OPD, and then RPD to LPD. Results: Among 3,083 patients who developed a POPF, 2,843 (92.2%) underwent OPD and 240 (7.8%) MIPD; of these, 25.0% were LPD (n = 60) and 75.0% RPD (n = 180). Grade B POPF was observed in 45.4% (n = 1,400), and grade C in 6.0% (n = 185). After PSM, MIPD patients had higher rates of CR-POPF (47.3% OPD vs. 54.4% MIPD, p = 0.037), as well as higher reoperation (9.1% vs. 15.3%, p = 0.006), delayed gastric emptying (29.2% vs. 35.8%, p = 0.041), and readmission rates (28.2% vs. 35.1%, p = 0.032). However, CR-POPF rates were comparable between LPD and RPD (56.8% vs. 49.3%, p = 0.408). Conclusion: The impact of POPF is more clinically pronounced after MIPD than OPD with a more complex postoperative course. The difference appears to be attributed to the minimally invasive environment itself as no difference was noted between LPD and RPD. A clear biological explanation of this clinical observation remains missing. Further studies are warranted.

7.
J Dent ; 148: 105212, 2024 Jun 25.
Artículo en Inglés | MEDLINE | ID: mdl-38936456

RESUMEN

OBJECTIVES: To investigate the effectiveness of different adjunctive local treatments combined with non-surgical periodontal therapy (NSPT) to reduce pocket depth (PD), gain clinical attachment level (CAL), and/or reduce glycated hemoglobin (HbA1c) in individuals with both type 2 diabetes mellitus (T2DM) and periodontitis in a systematic review and network meta-analysis. DATA SOURCES: Publications were searched in Cochrane databases, EMBASE, Google Scholar, MEDLINE, PubMed, opengrey.eu, and www. CLINICALTRIALS: gov up to May 29, 2024 with no language restriction. STUDY SELECTION: Only randomized controlled trials (RCTs) were included. Network meta-analysis utilized frequentist models. DATA: The network meta-analysis of 30 RCTs involving 1224 patients revealed that, in short-term (2-3 months) and medium-term (4-6 months), adjunctive local treatment involving statins or metformin significantly outperformed scaling and root planning (SRP) with/without additional interventions such as photodynamic and laser therapies (PDT/LT), phytotherapy, doxycycline, bisphosphonates, antibiotics, antiseptics, or placebo for reducing PD and/or gaining CAL. In the long-term (>6 months), statins yielded the most significant additional PD reduction and CAL gain, followed by antibiotics, compared to SRP with antiseptics or placebo. Only PDT/LT demonstrated significantly greater HbA1c reduction in the short term compared to SRP with/without statins, antiseptics, or placebo. CONCLUSION: This study moderately supports that adding metformin or statins locally to NSPT may enhance PD reduction and CAL gain compared to SRP with/without placebo. CLINICAL SIGNIFICANCE: Clinicians are guided to optimize adjunctive therapies, enhancing the health of patients with type 2 diabetes and periodontitis. A strategic approach is proposed to tackle systemic and oral health challenges simultaneously.

8.
JCI Insight ; 9(12)2024 May 21.
Artículo en Inglés | MEDLINE | ID: mdl-38912586

RESUMEN

Immune therapy is the new frontier of cancer treatment. Therapeutic radiation is a known inducer of immune response and can be limited by immunosuppressive mediators including cyclooxygenase-2 (COX2) that is highly expressed in aggressive triple negative breast cancer (TNBC). A clinical cohort of TNBC tumors revealed poor radiation therapeutic efficacy in tumors expressing high COX2. Herein, we show that radiation combined with adjuvant NSAID (indomethacin) treatment provides a powerful combination to reduce both primary tumor growth and lung metastasis in aggressive 4T1 TNBC tumors, which occurs in part through increased antitumor immune response. Spatial immunological changes including augmented lymphoid infiltration into the tumor epithelium and locally increased cGAS/STING1 and type I IFN gene expression were observed in radiation-indomethacin-treated 4T1 tumors. Thus, radiation and adjuvant NSAID treatment shifts "immune desert phenotypes" toward antitumor M1/TH1 immune mediators in these immunologically challenging tumors. Importantly, radiation-indomethacin combination treatment improved local control of the primary lesion, reduced metastatic burden, and increased median survival when compared with radiation treatment alone. These results show that clinically available NSAIDs can improve radiation therapeutic efficacy through increased antitumor immune response and augmented local generation of cGAS/STING1 and type I IFNs.


Asunto(s)
Proteínas de la Membrana , Transducción de Señal , Linfocitos T Citotóxicos , Animales , Proteínas de la Membrana/metabolismo , Ratones , Femenino , Transducción de Señal/efectos de los fármacos , Linfocitos T Citotóxicos/inmunología , Linfocitos T Citotóxicos/efectos de los fármacos , Neoplasias de la Mama Triple Negativas/patología , Neoplasias de la Mama Triple Negativas/inmunología , Neoplasias de la Mama Triple Negativas/tratamiento farmacológico , Neoplasias de la Mama Triple Negativas/radioterapia , Indometacina/farmacología , Indometacina/uso terapéutico , Línea Celular Tumoral , Humanos , Neoplasias Pulmonares/inmunología , Neoplasias Pulmonares/patología , Neoplasias Pulmonares/tratamiento farmacológico , Inhibidores de la Ciclooxigenasa/farmacología , Inhibidores de la Ciclooxigenasa/uso terapéutico , Nucleotidiltransferasas/metabolismo , Interferón Tipo I/metabolismo , Ciclooxigenasa 2/metabolismo , Linfocitos Infiltrantes de Tumor/inmunología , Linfocitos Infiltrantes de Tumor/efectos de los fármacos , Ratones Endogámicos BALB C
10.
JMIR AI ; 3: e51240, 2024 Jan 15.
Artículo en Inglés | MEDLINE | ID: mdl-38875566

RESUMEN

BACKGROUND: Pancreatic cancer is the third leading cause of cancer deaths in the United States. Pancreatic ductal adenocarcinoma (PDAC) is the most common form of pancreatic cancer, accounting for up to 90% of all cases. Patient-reported symptoms are often the triggers of cancer diagnosis and therefore, understanding the PDAC-associated symptoms and the timing of symptom onset could facilitate early detection of PDAC. OBJECTIVE: This paper aims to develop a natural language processing (NLP) algorithm to capture symptoms associated with PDAC from clinical notes within a large integrated health care system. METHODS: We used unstructured data within 2 years prior to PDAC diagnosis between 2010 and 2019 and among matched patients without PDAC to identify 17 PDAC-related symptoms. Related terms and phrases were first compiled from publicly available resources and then recursively reviewed and enriched with input from clinicians and chart review. A computerized NLP algorithm was iteratively developed and fine-trained via multiple rounds of chart review followed by adjudication. Finally, the developed algorithm was applied to the validation data set to assess performance and to the study implementation notes. RESULTS: A total of 408,147 and 709,789 notes were retrieved from 2611 patients with PDAC and 10,085 matched patients without PDAC, respectively. In descending order, the symptom distribution of the study implementation notes ranged from 4.98% for abdominal or epigastric pain to 0.05% for upper extremity deep vein thrombosis in the PDAC group, and from 1.75% for back pain to 0.01% for pale stool in the non-PDAC group. Validation of the NLP algorithm against adjudicated chart review results of 1000 notes showed that precision ranged from 98.9% (jaundice) to 84% (upper extremity deep vein thrombosis), recall ranged from 98.1% (weight loss) to 82.8% (epigastric bloating), and F1-scores ranged from 0.97 (jaundice) to 0.86 (depression). CONCLUSIONS: The developed and validated NLP algorithm could be used for the early detection of PDAC.

11.
Hernia ; 2024 Jun 18.
Artículo en Inglés | MEDLINE | ID: mdl-38890182

RESUMEN

PURPOSE: Although intraoperative music is purported to mitigate postoperative pain after some procedures, its application has never been explored in abdominal wall reconstruction (AWR). We sought to determine whether intraoperative music would decrease early postoperative pain following AWR. METHODS: We conducted a placebo-controlled, patient-, surgeon-, and assessor-blinded, randomized controlled trial at a single center between June 2022 and July 2023 including 321 adult patients undergoing open AWR with retromuscular mesh. Patients received noise-canceling headphones and were randomized 1:1 to patient-selected music or silence after induction, stratified by preoperative chronic opioid use. All patients received multimodal pain control. The primary outcome was pain (NRS-11) at 24 ± 3 h. The primary outcome was analyzed by linear regression with pre-specified covariates (chronic opioid use, hernia width, operative time, myofascial release, anxiety disorder diagnosis, and preoperative STAI-6 score). RESULTS: 178 patients were randomized to music, 164 of which were analyzed. 177 were randomized to silence, 157 of which were analyzed. At 24 ± 3 h postoperatively, there was no difference in the primary outcome of NRS-11 scores (5.18 ± 2.62 vs 5.27 ± 2.46, p = 0.75). After adjusting for prespecified covariates, the difference of NRS-11 scores at 24 ± 3 h between the music and silence groups remained insignificant (p = 0.83). There was no difference in NRS-11 or STAI-6 scores at 48 ± 3 and 72 ± 3 h, intraoperative sedation, or postoperative narcotic usage. CONCLUSION: For patients undergoing AWR, there was no benefit of intraoperative music over routine multimodal pain control for early postoperative pain reduction. TRIAL REGISTRATION: ClinicalTrials.gov: NCT05374096.

12.
Am Surg ; : 31348241256064, 2024 May 22.
Artículo en Inglés | MEDLINE | ID: mdl-38776896

RESUMEN

At Cleveland clinic, an incorrect surgical count triggers Code Rust; a protocol that mandates an intraoperative patient X-ray, staff radiology read, and discussion with the surgeon before the incision is closed. Code Rust calls from November 2014 to December 2022 were retrospectively reviewed. Realtime workflow and operative details of Code Rust cases were analyzed.1277 Code Rusts were identified. Average time from ordering the X-ray to final radiology report was 50 minutes, totalling $2,362,450.00 spent on operating room time. Code Rust was called twice as frequently during urgent or emergent cases, compared to elective. There were more staff in Code Rust rooms compared to non-Code Rust rooms. A foreign body on X-ray was identified in 42/1277 (3.3%) cases. Code Rust is a resource intensive process that is more common in emergent cases that involve multiple staff. While retained foreign bodies are identified in a small percentage of cases, the current system should be revisited to reduce operating time and expense.

13.
J Surg Educ ; 81(7): 912-917, 2024 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-38749811

RESUMEN

OBJECTIVE: Since the inception of Ken Lee Memorial Fellowship (KLMF) in 2013, our institution has achieved 10 years of trainee led sustainability projects. The ability of health care organizations to drive sustainability depends on organizational and human capacity. This qualitative study presents the first decade of sustainability fellows' projects, the challenges associated with implementing them, and the environmental and cost impact of these initiatives. DESIGN, SETTING, PARTICIPANTS: All residents in the General Surgery residency program at the Cleveland Clinic, a quaternary hospital, regardless of postgraduate year (PGY) level, are invited to apply for the KLMF program with a short project proposal. One fellow is selected per year. Each project since the program's inception was reviewed qualitatively, relying on data derived from observation, interview of prior fellows, and supervising staff, and analysis of documentation from the annual fellow presentation and abstract, Grand Rounds recording, and fellowship leadership. RESULTS: A targeted approach by each sustainability fellow is encouraged, with the following action cycle for change implementation throughout the 1-year fellowship: identification and discovery of an issue, collaborative planning of an intervention, implementation of the intervention, and evaluation. Projects range from water and waste reduction to education of surgical staff, with positive implications for environmental stewardship in our hospital. However, multiple barriers to completing, scaling, and maintaining sustainability initiatives remain, as demonstrated by challenges faced by our Ken Lee Fellows. CONCLUSIONS: Our goal is that this intensive educational experience within the framework of a graduate medical education curriculum will ensure future generations of surgeons who are thoughtful leaders in environmental stewardship.


Asunto(s)
Becas , Cirugía General , Liderazgo , Becas/organización & administración , Humanos , Cirugía General/educación , Internado y Residencia/organización & administración , Educación de Postgrado en Medicina , Conservación de los Recursos Naturales
15.
Clin Cancer Res ; 30(14): 2996-3005, 2024 Jul 15.
Artículo en Inglés | MEDLINE | ID: mdl-38718141

RESUMEN

PURPOSE: Treatment paradigms for isocitrate dehydrogenase (IDH)-mutant gliomas are rapidly evolving. Although typically indolent and responsive to initial treatment, these tumors invariably recur at a higher grade and require salvage treatment. Homozygous deletion of the tumor suppressor gene CDKN2A/B frequently emerges at recurrence in these tumors, driving poor patient outcomes. We investigated the effect of CDK-Rb pathway blockade on IDH-mutant glioma growth in vitro and in vivo using CDK4/6 inhibitors (CDKi). EXPERIMENTAL DESIGN: Cell viability, proliferation assays, and flow cytometry were used to examine the pharmacologic effect of two distinct CDKi, palbociclib and abemaciclib, in multiple patient-derived IDH-mutant glioma lines. Isogenic models were used to directly investigate the influence of CDKN2A/B status on CDKi sensitivity. Orthotopic xenograft tumor models were used to examine the efficacy and tolerability of CDKi in vivo. RESULTS: CDKi treatment leads to decreased cell viability and proliferative capacity in patient-derived IDH-mutant glioma lines, coupled with enrichment of cells in the G1 phase. CDKN2A inactivation sensitizes IDH-mutant glioma to CDKi in both endogenous and isogenic models with engineered CDKN2A deletion. CDK4/6 inhibitor administration improves survival in orthotopically implanted IDH-mutant glioma models. CONCLUSIONS: IDH-mutant gliomas with deletion of CDKN2A/B are sensitized to CDK4/6 inhibitors. These results support the investigation of the use of these agents in a clinical setting.


Asunto(s)
Aminopiridinas , Bencimidazoles , Proliferación Celular , Quinasa 4 Dependiente de la Ciclina , Quinasa 6 Dependiente de la Ciclina , Inhibidor p15 de las Quinasas Dependientes de la Ciclina , Inhibidor p16 de la Quinasa Dependiente de Ciclina , Glioma , Isocitrato Deshidrogenasa , Mutación , Piperazinas , Inhibidores de Proteínas Quinasas , Piridinas , Ensayos Antitumor por Modelo de Xenoinjerto , Humanos , Animales , Quinasa 4 Dependiente de la Ciclina/antagonistas & inhibidores , Quinasa 4 Dependiente de la Ciclina/genética , Quinasa 6 Dependiente de la Ciclina/antagonistas & inhibidores , Quinasa 6 Dependiente de la Ciclina/genética , Glioma/genética , Glioma/tratamiento farmacológico , Glioma/patología , Ratones , Inhibidor p16 de la Quinasa Dependiente de Ciclina/genética , Isocitrato Deshidrogenasa/genética , Isocitrato Deshidrogenasa/antagonistas & inhibidores , Bencimidazoles/farmacología , Inhibidor p15 de las Quinasas Dependientes de la Ciclina/genética , Aminopiridinas/farmacología , Inhibidores de Proteínas Quinasas/farmacología , Inhibidores de Proteínas Quinasas/uso terapéutico , Piperazinas/farmacología , Piperazinas/uso terapéutico , Proliferación Celular/efectos de los fármacos , Piridinas/farmacología , Piridinas/uso terapéutico , Línea Celular Tumoral , Eliminación de Gen , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/tratamiento farmacológico , Neoplasias Encefálicas/patología , Homocigoto
16.
Sci Adv ; 10(20): eado1463, 2024 May 17.
Artículo en Inglés | MEDLINE | ID: mdl-38758782

RESUMEN

A ketogenic diet (KD) is a high-fat, low-carbohydrate diet that leads to the generation of ketones. While KDs improve certain health conditions and are popular for weight loss, detrimental effects have also been reported. Here, we show mice on two different KDs and, at different ages, induce cellular senescence in multiple organs, including the heart and kidney. This effect is mediated through adenosine monophosphate-activated protein kinase (AMPK) and inactivation of mouse double minute 2 (MDM2) by caspase-2, leading to p53 accumulation and p21 induction. This was established using p53 and caspase-2 knockout mice and inhibitors to AMPK, p21, and caspase-2. In addition, senescence-associated secretory phenotype biomarkers were elevated in serum from mice on a KD and in plasma samples from patients on a KD clinical trial. Cellular senescence was eliminated by a senolytic and prevented by an intermittent KD. These results have important clinical implications, suggesting that the effects of a KD are contextual and likely require individual optimization.


Asunto(s)
Senescencia Celular , Dieta Cetogénica , Ratones Noqueados , Proteína p53 Supresora de Tumor , Animales , Proteína p53 Supresora de Tumor/metabolismo , Proteína p53 Supresora de Tumor/genética , Ratones , Humanos , Inhibidor p21 de las Quinasas Dependientes de la Ciclina/metabolismo , Inhibidor p21 de las Quinasas Dependientes de la Ciclina/genética , Proteínas Quinasas Activadas por AMP/metabolismo , Proteínas Proto-Oncogénicas c-mdm2/metabolismo , Masculino , Especificidad de Órganos
17.
Res Sq ; 2024 Apr 03.
Artículo en Inglés | MEDLINE | ID: mdl-38645113

RESUMEN

DNA methylation at cytosine bases of eukaryotic DNA (5-methylcytosine, 5mC) is a heritable epigenetic mark that can regulate gene expression in health and disease. Enzymes that metabolize 5mC have been well-characterized, yet the discovery of endogenously produced signaling molecules that regulate DNA methyl-modifying machinery have not been described. Herein, we report that the free radical signaling molecule nitric oxide (NO) can directly inhibit the Fe(II)/2-OG-dependent DNA demethylases ten-eleven translocation (TET) and human AlkB homolog 2 (ALKBH2). Physiologic NO concentrations reversibly inhibited TET and ALKBH2 demethylase activity by binding to the mononuclear non-heme iron atom which formed a dinitrosyliron complex (DNIC) preventing cosubstrates (2-OG and O2) from binding. In cancer cells treated with exogenous NO, or cells endogenously synthesizing NO, there was a global increase in 5mC and 5-hydroxymethylcytosine (5hmC) in DNA, the substrates for TET, that could not be attributed to increased DNA methyltransferase activity. 5mC was also elevated in NO-producing cell-line-derived mouse xenograft and patient-derived xenograft tumors. Genome-wide DNA methylome analysis of cells chronically treated with NO (10 days) demonstrated enrichment of 5mC and 5hmC at gene-regulatory loci which correlated to changes in the expression of NO-regulated tumor-associated genes. Regulation of DNA methylation is distinctly different from canonical NO signaling and represents a novel epigenetic role for NO.

18.
Front Physiol ; 15: 1358850, 2024.
Artículo en Inglés | MEDLINE | ID: mdl-38601214

RESUMEN

The human epidermal growth factor receptor (HER) family consists of four members, activated by two families of ligands. They are known for mediating cell-cell interactions in organogenesis, and their deregulation has been associated with various cancers, including breast and esophageal cancers. In particular, aberrant epidermal growth factor receptor (EGFR) and HER2 signaling drive disease progression and result in poorer patient outcomes. Nitric oxide (NO) has been proposed as an alternative activator of the HER family and may play a role in this aberrant activation due to its ability to induce s-nitrosation and phosphorylation of the EGFR. This review discusses the potential impact of NO on HER family activation and downstream signaling, along with its role in the efficacy of therapeutics targeting the family.

20.
Am J Surg ; 234: 99-104, 2024 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-38580567

RESUMEN

INTRODUCTION: Abdominal surgery following transversus abdominis release (TAR) procedure commonly involves incisions through the previously implanted mesh, potentially creating vulnerabilities for hernia recurrence. Despite the popularity of the TAR procedure, current literature regarding post-AWR surgeries is limited. This study aims to reveal the incidence and outcomes of post-TAR non-hernia-related abdominal surgeries of any kind. METHODS: Adult patients who underwent non-hernia-related abdominal surgery following ventral hernia repair with concurrent TAR procedure and permanent synthetic mesh in the Cleveland Clinic Center for Abdominal Core Health between January 2014 and January 2022 were queried from a prospectively collected database in the Abdominal Core Health Quality Collaborative. We evaluated 30-day wound morbidity, perioperative complications, and long-term hernia recurrence. RESULTS: A total of 1137 patients who underwent TAR procedure were identified, with 53 patients (4.7%) undergoing subsequent non-hernia-related abdominal surgery post-TAR. Small bowel obstruction was the primary indication for reoperation (22.6%), and bowel resection was the most frequent procedure (24.5%). 49.1% of the patients required urgent or emergent surgery, with the majority (70%) having open procedures. Fascia closure was achieved by absorbable sutures in 50.9%, and of the open cases, fascia closure was achieved by running sutures technique in 35.8%. 20.8% experienced SSO, the SSOPI rate was 11.3%, and 26.4% required more than a single reoperation. A total of 88.7% were available for extended follow-up, spanning 17-30 months, resulting in a 36.1% recurrent hernia diagnosis rate. CONCLUSIONS: Abdominal surgery following TAR surgery is associated with significant comorbidities and significantly impacts hernia recurrence rates. Our study findings underscore the significance of making all efforts to minimize reoperations after TAR procedure and offers suggestions on managing the abdominal wall of these complex cases.


Asunto(s)
Músculos Abdominales , Pared Abdominal , Hernia Ventral , Herniorrafia , Complicaciones Posoperatorias , Reoperación , Mallas Quirúrgicas , Humanos , Masculino , Femenino , Persona de Mediana Edad , Hernia Ventral/cirugía , Herniorrafia/métodos , Reoperación/estadística & datos numéricos , Pared Abdominal/cirugía , Complicaciones Posoperatorias/epidemiología , Complicaciones Posoperatorias/etiología , Anciano , Recurrencia , Estudios Retrospectivos , Adulto
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