Tofacitinib Regulates Endostatin via Effects on CD147 and Cathepsin S.

Angiogenesis is critical for rheumatoid arthritis (RA) progression. The effects of tofacitinib, a JAK-STAT inhibitor used for RA treatment, on angiogenesis in RA are unclear. We, therefore, evaluated the levels of angiogenic factors in two systems of a human co-culture of fibroblast (HT1080) and monocytic (U937) cell lines treated with tofacitinib and in serum samples from RA patients before and after six months of tofacitinib treatment. Tofacitinib reduced CD147 levels, matrix metalloproteinase-9 (MMP-9) activity, and angiogenic potential but increased endostatin levels and secreted proteasome 20S activity. In vitro, tofacitinib did not change CD147 mRNA but increased miR-146a-5p expression and reduced STAT3 phosphorylation. We recently showed that CD147 regulates the ability of MMP-9 and secreted proteasome 20S to cleave collagen XVIIIA into endostatin. We show here that tofacitinib-enhanced endostatin levels are mediated by CD147, as CD147-siRNA or an anti-CD147 antibody blocked proteasome 20S activity. The correlation between CD147 and different disease severity scores supported this role. Lastly, tofacitinib reduced endostatin' s degradation by inhibiting cathepsin S activity and recombinant cathepsin S reversed this in both systems. Thus, tofacitinib inhibits angiogenesis by reducing pro-angiogenic factors and enhancing the anti-angiogenic factor endostatin in a dual effect mediated partly through CD147 and partly through cathepsin S.

Gain-of-function variants in CLCN7 cause hypopigmentation and lysosomal storage disease.

Together with its ß-subunit OSTM1, ClC-7 performs 2Cl-/H+ exchange across lysosomal membranes. Pathogenic variants in either gene cause lysosome-related pathologies, including osteopetrosis and lysosomal storage. CLCN7 variants can cause recessive or dominant disease. Different variants entail different sets of symptoms. Loss of ClC-7 causes osteopetrosis and mostly neuronal lysosomal storage. A recently reported de novo CLCN7 mutation (p.Tyr715Cys) causes widespread severe lysosome pathology (hypopigmentation, organomegaly, and delayed myelination and development, "HOD syndrome"), but no osteopetrosis. We now describe two additional HOD individuals with the previously described p.Tyr715Cys and a novel p.Lys285Thr mutation, respectively. Both mutations decreased ClC-7 inhibition by PI(3,5)P2 and affected residues lining its binding pocket, and shifted voltage-dependent gating to less positive potentials, an effect partially conferred to WT subunits in WT/mutant heteromers. This shift predicts augmented pH gradient-driven Cl- uptake into vesicles. Overexpressing either mutant induced large lysosome-related vacuoles. This effect depended on Cl-/H+-exchange, as shown using mutants carrying uncoupling mutations. Fibroblasts from the p.Y715C patient also displayed giant vacuoles. This was not observed with p.K285T fibroblasts probably due to residual PI(3,5)P2 sensitivity. The gain of function caused by the shifted voltage-dependence of either mutant likely is the main pathogenic factor. Loss of PI(3,5)P2 inhibition will further increase current amplitudes, but may not be a general feature of HOD. Overactivity of ClC-7 induces pathologically enlarged vacuoles in many tissues, which is distinct from lysosomal storage observed with the loss of ClC-7 function. Osteopetrosis results from a loss of ClC-7, but osteoclasts remain resilient to increased ClC-7 activity.

Conversion of sleeve gastrectomy to Roux-en-Y gastric bypass: impact on reflux and weight loss.

BACKGROUND: Sleeve gastrectomy (SG) is the most commonly performed weight loss operation, and its 2 most common complications are postoperative reflux and weight recurrence. There is limited evidence to guide decision-making in treating these conditions. OBJECTIVES: To determine the efficacy of conversion of SG to Roux-en-Y gastric bypass (RYGB) for GERD management and weight loss. SETTING: Forty-one hospitals in Michigan. METHODS: We conducted a retrospective cohort study examining patients who underwent conversion of SG to RYGB from 2014 to 2022. The primary outcomes were changes in GERD-HRQL scores, anti-reflux medication use, and weight from baseline to 1 year after conversion. Secondary outcomes included 30-day postoperative complications and resource utilization. RESULTS: Among 2133 patients undergoing conversion, 279 (13%) patients had baseline and 1-year GERD-HRQL survey data and anti-reflux medication data. GERD-HRQL scores decreased significantly from 24.6 to 6.6 (P < .01). Among these, 207 patients (74%) required anti-reflux medication at baseline, with only 76 patients (27%) requiring anti-reflux medication at 1 year postoperatively (P < .01). Of the 380 patients (18%) with weight loss data, mean weight decreased by 68.4lbs, with a 24.3% decline in total body weight and 51.5% decline in excess body weight. In terms of 30-day complications, 308 (14%) patients experienced any complication and 89 (4%) experienced a serious complication, but there were no leaks, perforations, or deaths. Three-hundred and fifty-five (17%) patients presented to the emergency department and 64 (3%) patients underwent reoperation. CONCLUSIONS: This study represents the largest reported experience with conversion from SG to RYGB. We found that conversion to RYGB is associated with significant improvement in GERD symptoms, reduction in anti-reflux medication use, and significant weight loss and is therefore an effective treatment for GERD and weight regain after SG. However, the risks and benefits of conversion surgery should be carefully considered, especially in patients with significant comorbidity burden.

Structural Racism, Residential Segregation, and Exposure to Trauma: The Persistent Impact of Redlining.

INTRODUCTION: As part of New Deal era federal housing policy, the Home Owners Loan Corporation (HOLC) developed maps grading US neighborhoods by perceived financial security. Neighborhoods with high concentrations of racial and ethnic minorities were deemed financially unstable and denied federal investment, a practice colloquially known as redlining. The aim of this study was to assess the association of historical redlining within Austin, Texas to spatial patterns of penetrating traumatic injury. METHODS: Retrospective cross sectional study utilizing data from violent penetrating trauma admissions between January 1, 2014 - December 31, 2021, at the single Level 1 trauma center in Austin, Texas. Using ArcGIS, addresses where the injury took place were geocoded and spatial joining was used to match them to their corresponding census tract, for which 1935 HOLC financial designations are classified as: "Hazardous", "Definitely Declining", "Still Desirable", "Best", or "Non HOLC Graded". Tracts with designations of "Hazardous" and "Definitely Declining" were categorized as Redlined. The adjusted incidence rate ratio comparing rates of penetrating trauma among historically Redlined vs. Not Redlined and Not Graded census tracts was calculated. RESULTS: 1,404 violent penetrating trauma admissions were identified for the study period, of which 920 occurred within the county of interest. Among these, 5% occurred in census tracts that were Not Redlined, 13% occurred in Redlined tracts, and 82% occurred in non HOLC graded tracts. When adjusting for differences in current census tract demographics and social vulnerability, historically Redlined areas experienced a higher rate of penetrating traumatic injury (Not Redlined IRR = 0.42, 95% CI 0.19-0.94, p = 0.03; Not Graded IRR = 0.15, 95% CI 0.07-0.29, p < 0.001). CONCLUSIONS: Neighborhoods unfavorably classified by HOLC in 1935 continue to experience a higher incidence rate of violent penetrating trauma today. These results underscore the persistent impacts of structural racism and of historical residential segregation policies on exposure to trauma. LEVEL OF EVIDENCE: Level IV, Prognostic and Epidemiological.

Polycarbonate-Based Copolymer Micelles as Biodegradable Carriers of Anticancer Podophyllotoxin or Juniper Extracts.

Podophyllotoxin (PPT) is used in the industrial production of efficient anticancer, antiviral and other drugs. Sinopodophyllum hexandrum or Podophyllum peltatum are natural sources of PPT, but at present they are considered as endangered species. Their PPT content is variable, depending on the growing conditions. Searching for new sources of PPT, some representatives of the genus Juniperus were found to exhibit efficient PPT biosynthesis. However, PPT is highly toxic and poorly soluble in water compound, which limits its clinical applications. In this connection, amphiphilic polymer micelles are considered to be suitable PPT carriers, aimed at increase in water solubility and decrease in toxicity. The present research deals with the evaluation of MPEG-polycarbonate block copolymer micelles loaded with PPT or juniper extracts. The active component-loaded polymer nanocarriers were characterized by dynamic and electrophoretic light scattering, as well as by transmission electron microscopy. The active component loading efficiency and loading capacity were also determined. Highly efficient antiproliferative activity of the loaded micelles was determined in a panel of cancer cell lines. The obtained amphiphilic nanocarriers, loaded with PPT-containing bioactive components, have application in future in vivo preclinical trials of their pharmacokinetics and pharmacodynamics as potential therapeutical agents in the prospective nanomedicine.

Soluble CD147 regulates endostatin via its effects on the activities of MMP-9 and secreted proteasome 20S.

During progression of rheumatoid arthritis (RA), angiogenesis provides oxygen and nutrients for the cells' increased metabolic demands and number. To turn on angiogenesis, pro-angiogenic factors must outweigh anti-angiogenic factors. We have previously shown that CD147/extracellular matrix metalloproteinase inducer (EMMPRIN) can induce the expression of the pro-angiogenic factors vascular endothelial growth factor (VEGF) and matrix metallopeptidase 9 (MMP-9) in a co-culture of the human HT1080 fibrosarcoma and U937 monocytic-like cell lines. However, whether CD147 influences anti-angiogenic factors was not known. We now show that relative to single cultures, the co-culture of these cells not only enhanced pro-angiogenic factors but also decreased the anti-angiogenic factors endostatin and thrombospondin-1 (Tsp-1), generally increasing the angiogenic potential as measured by a wound assay. Using anti-CD147 antibody, CD147 small interfering RNA (siRNA), and recombinant CD147, we demonstrate that CD147 hormetically regulates the generation of endostatin but has no effect on Tsp-1. Since endostatin is cleaved from collagen XVIII (Col18A), we applied different protease inhibitors and established that MMP-9 and proteasome 20S, but not cathepsins, are responsible for endostatin generation. MMP-9 and proteasome 20S collaborate to synergistically enhance endostatin generation, and in a non-cellular system, CD147 enhanced MMP-9 activity and hormetically regulated proteasome 20S activity. Serum samples obtained from RA patients and healthy controls mostly corroborated these findings, indicating clinical relevance. Cumulatively, these findings suggest that secreted CD147 mediates a possibly allosteric effect on MMP-9 and proteasome 20S activities and can serve as a switch that turns angiogenesis on or off, depending on its ambient concentrations in the microenvironment.

Biopolymeric Nanogel as a Drug Delivery System for Doxorubicin-Improved Drug Stability and Enhanced Antineoplastic Activity in Skin Cancer Cells.

In this study, doxorubicin was loaded in a chitosan-albumin nanogel with the aim of improving its stability and exploring the potential of the system in the treatment of skin cancer. Infrared spectroscopy and X-ray diffraction confirmed the encapsulation of the drug. Transmission electron microscopy revealed the spherical shape of the nanogel particles. The drug-loaded nanogel was characterized with a small diameter of 29 nm, narrow polydispersity (0.223) and positive zeta potential (+34 mV). The exposure of encapsulated doxorubicin to light (including UV irradiation and daylight) did not provoke any degradation, whereas the nonencapsulated drug was significantly degraded. In vitro studies on keratinocytes (HaCaT) and epidermoid squamous skin carcinoma cells (A-431) disclosed that the encapsulated doxorubicin was more cytotoxic on both cell lines than the pure drug was. More importantly, the cytotoxic concentration of encapsulated doxorubicin in carcinoma cells was approximately two times lower than that in keratinocytes, indicating that it would not affect them. Thus, the loading of doxorubicin into the developed chitosan-albumin nanogel definitely stabilized the drug against photodegradation and increased its antineoplastic effect on the skin cancer cell line.

Racial disparities in endometrial cancer: Where are we after 26 years?

INTRODUCTION: Endometrial cancer is the most commonly diagnosed female genital tract malignancy in the United States of America. Racial disparities surrounding this particular disease have been extensively investigated for over 26-years. We sought to determine if research in this area has led to any significant improvements in this disparity. METHODS: We performed a rapid systematic review of English language publications on racial disparities in endometrial cancer among African American (AAW) and white American women (WAW), from 1997 to 2023. We looked at trends in incidence and survival; impact of known poor prognostic factors (stage at diagnosis, histological subtypes, grade); co-morbidities; differences in treatment (surgery, radiation and chemotherapy); socioeconomic factors; differences in biological and genetic markers; and policies/declarations. RESULTS: During the period under review (1997-2023), there was a notable increase in both disease incidence (39%) and mortality (26%) rates for AAW, in comparison to WAW among whom the incidence rates increased by 2% and mortality rates rose, but 9% less than for AAW. It should be noted that the current incidence rate of 29.4% in AAW represent a reversal of what is was 26-years ago, when the incidence rate was 17.8%. In comparison to WAW, AAW had a higher prevalence of poor prognostic variables, more co-morbidities, lower income levels, less insurance coverage, and were more frequently under treated with surgery, chemotherapy and radiation. To date no actionable molecular/genetic markers have been identified. We were unable to locate any published recommendations or active programs of implementation strategies/policies designed to effectively mitigate the documented racial disparity. CONCLUSION: Racial disparities in disease incidence and mortality in endometrial cancer rates between WAW and AAW have widened during a 26-year period of robust research, suggesting that current research alone is not enough to eliminate this disparity. Based on this rapid systematic review we have identified and analyzed the impact of causation variables on this disparity. Additionally, we have made strong and pertinent recommendations for the benefit of mitigating this escalating racial disparity.

The impact of Black founding fathers on the specialty of gynecologic oncology.

INTRODUCTION: The formative period of the specialty of gynecologic oncology was from 1968 to 1972 and became a board-certified specialty in 1973. During this formation there were no Black physicians participating in this process. We chronicle and document the incorporation of the first three board-certified Black physicians in the specialty of gynecologic oncology here for historical purposes. METHODS: We highlight the hostile climate experienced by Black physicians before and during the formation of gynecologic oncology, review the acceptance and training of the first three Black physicians in the specialty and recognize their significant contributions to the field. RESULTS: The biographies and the narrative of these men describe their impact and contribution to medicine. We chronicle the historic presence of the first board-certified Black gynecologic oncologists and pelvic surgeons in the United States. CONCLUSION: These three men represent the Black Founding Fathers of gynecologic oncology. Their perseverance in the face of adversity and commitment to excellence have left an indelible impact on the institutions that they developed, the individuals that they trained, and the patients that they served.

Significantly Improved Cold Preservation of Rat Hind Limb Vascularized Composite Allografts Using the New PrC-210 Free Radical Scavenger.

Vascularized composite allotransplantation (VCA) represents a promising reconstructive solution primarily conducted to improve quality of life. However, tissue damage caused by cold-ischemia (CI) storage prior to transplant represents a major factor limiting widespread application. This study investigates the addition of the novel free radical scavenger PrC-210 to UW Organ Preservation Solution (UW Solution) to suppress CI-induced skeletal muscle injury in a rat hind limb amputation model. Lewis rats received systemic perfusion of UW solution +/- PrC-210 (0 mM control, 10 mM, 20 mM, 30 mM, or 40 mM), followed by bilateral transfemoral amputation. Limbs were stored in 40 mL of the same perfusate at 4 °C for 48 h. Muscle punch biopsies were taken at set times over the 48 h cold-storage period and analyzed for caspase-3,7 activity, cytochrome C levels, and qualitative histology. A single 15 s perfusion of PrC-210-containing UW Solution conferred a dose-dependent reduction in CI-induced muscle cell death over 48 h. In the presence of PrC-210, muscle cell mitochondrial cytochrome C release was equivalent to 0 h controls, with profound reductions in the caspase-3,7 apoptotic marker that correlated with limb histology. PrC-210 conferred complete prevention of ROS-induced mitochondrial lysis in vitro, as measured by cytochrome C release. We conclude that the addition of 30 mM PrC210 to UW Solution conferred the most consistent reduction in CI limb damage, and it warrants further investigation for clinical application in the VCA setting.

Exploring the multifaceted role of NRF2 in brain physiology and cancer: A comprehensive review.

Chronic oxidative stress plays a critical role in the development of brain malignancies due to the high rate of brain oxygen utilization and concomitant production of reactive oxygen species. The nuclear factor-erythroid-2-related factor 2 (NRF2), a master regulator of antioxidant signaling, is a key factor in regulating brain physiology and the development of age-related neurodegenerative diseases. Also, NRF2 is known to exert a protective antioxidant effect against the onset of oxidative stress-induced diseases, including cancer, along with its pro-oncogenic activities through regulating various signaling pathways and downstream target genes. In glioblastoma (GB), grade 4 glioma, tumor resistance, and recurrence are caused by the glioblastoma stem cell population constituting a small bulk of the tumor core. The persistence and self-renewal capacity of these cell populations is enhanced by NRF2 expression in GB tissues. This review outlines NRF2's dual involvement in cancer and highlights its regulatory role in human brain physiology and diseases, in addition to the development of primary brain tumors and therapeutic potential, with a focus on GB.

Blocking Formation of Neurotoxic Reactive Astrocytes is Beneficial Following Stroke.

Microglia and astrocytes play an important role in the neuroinflammatory response and contribute to both the destruction of neighboring tissue as well as the resolution of inflammation following stroke. These reactive glial cells are highly heterogeneous at both the transcriptomic and functional level. Depending upon the stimulus, microglia and astrocytes mount a complex, and specific response composed of distinct microglial and astrocyte substates. These substates ultimately drive the landscape of the initiation and recovery from the adverse stimulus. In one state, inflammation- and damage-induced microglia release tumor necrosis factor (TNF), interleukin 1α (IL1α), and complement component 1q (C1q), together 'TIC'. This cocktail of cytokines drives astrocytes into a neurotoxic reactive astrocyte (nRA) substate. This nRA substate is associated with loss of many physiological astrocyte functions (e.g., synapse formation and maturation, phagocytosis, among others), as well as a gain-of-function release of neurotoxic long-chain fatty acids which kill neighboring cells. Here we report that transgenic removal of TIC led to reduction of gliosis, infarct expansion, and worsened functional deficits in the acute and delayed stages following stroke. Our results suggest that TIC cytokines, and likely nRAs play an important role that may maintain neuroinflammation and inhibit functional motor recovery after ischemic stroke. This is the first report that this paradigm is relevant in stroke and that therapies against nRAs may be a novel means to treat patients. Since nRAs are evolutionarily conserved from rodents to humans and present in multiple neurodegenerative diseases and injuries, further identification of mechanistic role of nRAs will lead to a better understanding of the neuroinflammatory response and the development of new therapies.

Ready Day One: What Residents and Program Directors Think is Needed for a Successful Transition to Residency.

OBJECTIVE: To evaluate perceived gaps in preparedness, current on-boarding practices, and need for specialty wide resources in the transition to residency training in obstetrics and gynecology (OB/GYN) DESIGN, SETTING, AND PARTICIPANTS: A cross-sectional survey of current U.S. OB/GYN residents and program directors (PDs) at the time of the resident in-training exam was conducted in 2022. Both groups provide demographic information and identified specific knowledge, skills, and abilities in need of more preparation at the start of residency. PDs were queried on perceptions of readiness for their current first year class, educational on-boarding practices, and their preference for standardized curricular materials and assessment tools. Chi-squared and Kruskal-Wallis tests were used to compare perceptions of skills deficits between PDs and residents, and the relationship of preparedness to program type and resident year in training. RESULTS: Response rates for residents and program directors were 64.9% and 72.6% respectively. A majority (115/200, 57.5%) of program directors agreed or strongly agreed with the statement, "In general, I feel that my new interns are well prepared for residency when they arrive at my program." Both groups agreed that basic suturing and ultrasound skills were deficits. Residents identified a need for better preparation in management of inpatient issues while PDs identified time management skills as lacking. There was considerable heterogeneity of program on-boarding practices across the specialty. Most PDs agreed or strongly agreed that a standardized curriculum (80.5%, 161/200) and assessment tools (75.3%, 150/199) would be helpful. CONCLUSION: OBGYN PDs feel that not all residents arrive prepared for residency and overwhelmingly support the development of standardized transition curricular and assessment tools, similar to the curriculum developed in general surgery. Based on input from PDs and residents, early curricular efforts should focus on basic surgical, ultrasound, and time management skills and on management of inpatient issues.

Outlooks on using a mobile health intervention for supportive pain management for children and adolescents with cancer: a qualitative study.

BACKGROUND: Considerable improvements in the prognosis of pediatric cancer patients have been achieved over recent decades due to advances in treatment. Nevertheless, as the most common and distressing health issue for pediatrics with cancer, cancer-related pain is still a significant hurdle that impedes patients' journey to recovery, compromises their quality of life, and delays the positive outcome and effectiveness of their treatments. PURPOSE: Taking into consideration that acceptability studies are imperative for the design, evaluation, and implementation of healthcare interventions, this study aims to explore pediatric oncology patients' readiness to use a mobile health application that emphasizes social assistance and peer support in addition to conventional pain management methods. DESIGN AND METHODS: This study followed the Qualitative description approach. Twelve participants were chosen based on purposive sampling and maximum variation sampling. Interviews were analyzed using the conventional content analysis. RESULTS: Analysis of the interviews revealed four major categories: (A) The need for connectedness; (B) An innovative way to connect yet fearful; (C) A 3D approach; (D) Fears of the unfamiliar. CONCLUSIONS: This study is the first in Lebanon and the region to undertake an initiative towards introducing technology for pain assessment and management of children with cancer through a dedicated digital platform. The study results attested to the acceptability and potential utilization of this platform by children with cancer. PRACTICE IMPLICATIONS: Nurses need to be trained to play an essential role in teaching children with cancer about the significance of social support and assisting them to establish their social support network. Children with cancer are encouraged to voice out their need for help. Our proposed application can create an enabling environment to harness the power of social support and provide children with cancer the opportunity to connect on a deeper level in a supportive and pity-free space.

CRISPR screens decode cancer cell pathways that trigger γδ T cell detection.

γδ T cells are potent anticancer effectors with the potential to target tumours broadly, independent of patient-specific neoantigens or human leukocyte antigen background1-5. γδ T cells can sense conserved cell stress signals prevalent in transformed cells2,3, although the mechanisms behind the targeting of stressed target cells remain poorly characterized. Vγ9Vδ2 T cells-the most abundant subset of human γδ T cells4-recognize a protein complex containing butyrophilin 2A1 (BTN2A1) and BTN3A1 (refs. 6-8), a widely expressed cell surface protein that is activated by phosphoantigens abundantly produced by tumour cells. Here we combined genome-wide CRISPR screens in target cancer cells to identify pathways that regulate γδ T cell killing and BTN3A cell surface expression. The screens showed previously unappreciated multilayered regulation of BTN3A abundance on the cell surface and triggering of γδ T cells through transcription, post-translational modifications and membrane trafficking. In addition, diverse genetic perturbations and inhibitors disrupting metabolic pathways in the cancer cells, particularly ATP-producing processes, were found to alter BTN3A levels. This induction of both BTN3A and BTN2A1 during metabolic crises is dependent on AMP-activated protein kinase (AMPK). Finally, small-molecule activation of AMPK in a cell line model and in patient-derived tumour organoids led to increased expression of the BTN2A1-BTN3A complex and increased Vγ9Vδ2 T cell receptor-mediated killing. This AMPK-dependent mechanism of metabolic stress-induced ligand upregulation deepens our understanding of γδ T cell stress surveillance and suggests new avenues available to enhance γδ T cell anticancer activity.

Adrenal Ganglioneuroma: Diagnosis, Presentation, and Management of a Rare Tumor.

Adrenal ganglioneuromas are rare tumors arising from sympathetic ganglion cells that may present similarly to other adrenal tumors, making preoperative diagnosis challenging. We present a case of a young woman with a history of Hashimoto's thyroiditis who presented with hypertension and headaches. An abdominal CT scan revealed a large left adrenal mass, and while laboratory tests for catecholamines and metanephrines were normal, the suspicion for pheochromocytoma remained high given the size of the mass and persistent hypertension. The patient was started on alpha-blockers and beta-blockers in preparation for surgical removal. Pathology revealed a mature ganglioneuroma without evidence of malignancy, and postoperative blood pressure was normalized. We hypothesize that vessel compression from the large mass created functional stenosis, resulting in persistent hypertension. This case highlights the importance of a thorough workup for hypertension in young adults and routine preventative care visits to avoid delayed management. Adrenalectomy with histopathological examination remains the gold standard for treatment and diagnosis, and patients have a good prognosis following resection, with minimal need for recurrent therapy.

2022 ACC/AHA guideline for the diagnosis and management of aortic disease: A report of the American Heart Association/American College of Cardiology Joint Committee on Clinical Practice Guidelines.

AIM: The "2022 ACC/AHA Guideline for the Diagnosis and Management of Aortic Disease" provides recommendations to guide clinicians in the diagnosis, genetic evaluation and family screening, medical therapy, endovascular and surgical treatment, and long-term surveillance of patients with aortic disease across its multiple clinical presentation subsets (ie, asymptomatic, stable symptomatic, and acute aortic syndromes). METHODS: A comprehensive literature search was conducted from January 2021 to April 2021, encompassing studies, reviews, and other evidence conducted on human subjects that were published in English from PubMed, EMBASE, the Cochrane Library, CINHL Complete, and other selected databases relevant to this guideline. Additional relevant studies, published through June 2022 during the guideline writing process, were also considered by the writing committee, where appropriate. STRUCTURE: Recommendations from previously published AHA/ACC guidelines on thoracic aortic disease, peripheral artery disease, and bicuspid aortic valve disease have been updated with new evidence to guide clinicians. In addition, new recommendations addressing comprehensive care for patients with aortic disease have been developed. There is added emphasis on the role of shared decision making, especially in the management of patients with aortic disease both before and during pregnancy. The is also an increased emphasis on the importance of institutional interventional volume and multidisciplinary aortic team expertise in the care of patients with aortic disease.

Transient Thyroiditis Followed by Exacerbation of Hypothyroidism After Immune Checkpoint Inhibitor Therapy (Nivolumab and Ipilimumab) in a Patient With Pre-existing Autoimmune Hypothyroidism: A Case Report.

Treatment with immune checkpoint inhibitors has improved the prognosis of solid tumors. However, immune-related adverse events (IRAEs), including exacerbation of pre-existing autoimmune disease, are common and have become more frequent with combination therapy. The literature is scanty regarding reports of the use of combination immune checkpoint therapy in patients with pre-existing autoimmune hypothyroidism. We report a case of a man with a history of hypothyroidism, who developed transient thyroiditis, characterized by a thyrotoxic phase followed by a severe hypothyroid phase soon after receiving combination therapy (nivolumab and ipilimumab) for the treatment of a malignant pleural mesothelioma. He had been on a stable low dose of levothyroxine for 12 years prior to this episode. His levothyroxine requirement markedly increased soon after the episode of immune checkpoint inhibitor-induced thyroiditis. Immune checkpoint inhibitors can cause destructive thyroiditis followed by exacerbation of hypothyroidism in patients with pre-existing autoimmune hypothyroidism, such that patients end up on a higher dose of levothyroxine. This case will add to the growing literature regarding thyroid IRAEs associated with the use of immune checkpoint inhibitors in patients with pre-existing autoimmune thyroid disease.

Gynaecologic oncology surgical cancellations in Zambia.

Introduction: Cancellations of elective surgery in low-and middle-income countries (LMIC) are common and a major hindrance for patients who are in need of surgical therapeutic modalities. This is especially important in the context of scaling up needed surgical interventions for gynaecological cancer care. There is a knowledge gap in the literature related to cancellation of gynaecologic oncology surgeries in LMIC, where there is enormous need for this specific cancer surgical capacity. We report in an observational descriptive fashion, our experience at the UTH/CDH in Lusaka, Zambia, on the causes of surgical cancellations in gynaecologic oncology. Methods: From January 1, 2021 through June 31, 2023, we retrospectively evaluated the surgical registry for gynaecologic oncology at the UTH/CDH in Lusaka, Zambia to assess the number and causes of surgical cancellations. Results: There were a total of 66 (16.96%) surgical cancellations out of 389 scheduled gynaecologic oncology cases. Lack of available blood and/or low haemoglobin was the most frequent cause of surgical cancellations, 27 cases (40.90%). Conclusion: We highlight in our series that the lack of blood, leading to surgical cancellations was the most frequent impediment related to performing scheduled gynaecologic oncology surgical procedures. As gynaecologic oncology services scale up in LMIC, given the radical nature of surgery and its association with blood loss, it is incumbent on the entire clinical ecosystem to address this issue and to develop mitigating strategies, specific to their respective resource setting.

Micellar Curcumin Substantially Increases the Antineoplastic Activity of the Alkylphosphocholine Erufosine against TWIST1 Positive Cutaneous T Cell Lymphoma Cell Lines.

Cutaneous T-cell lymphoma (CTCL) is a rare form of cancer with local as well as systemic manifestations. Concomitant bacterial infections increase morbidity and mortality rates due to impaired skin barrier and immune deficiency. In the current study, we demonstrated that the in vitro anti-lymphoma potential of erufosine is diminished by TWIST1 expression and micellar curcumin substantially increases its antineoplastic activity. Pharmacokinetic analysis showed that the micellar curcumin (MCRM) used in our study was characterized by low zeta potential, slow release of curcumin, and fast cell membrane penetration. The combination ratio 1:4 [erufosine:MCRM] achieved strong synergism by inhibiting cell proliferation and clonogenicity. The combined antiproliferative effects were calculated using the symbolic mathematical software MAPLE 15. The synergistic combination strongly decreased the expression of TWIST1 and protein kinase B/Akt as proven by western blotting. Significant reductions in NF-κB activation, induction of apoptosis, and altered glutathione levels were demonstrated by corresponding assays. In addition, the synergistic combination enhanced the anti-staphylococcal activity and prevented biofilm formation, as shown by crystal violet staining. Taken together, the above results show that the development of nanotechnological treatment modalities for CTCL, based on rational drug combinations exhibiting parallel antineoplastic and antibacterial effects, may prove efficacious.