Poor Tolerance Research Articles

OGC SO35 - Capsule-sponge assessment of long segment Barrett's Oesophagus

Abstract Background Capsule-sponge technology is increasingly utilised in assessment of reflux, though NICE still recommends its usage for surveillance of Barrett's Oesophagus to be conducted carefully. Our hospital has utilised capsule-sponge technology for two years in the surveillance of Barrett's Oesophagus, whilst adhering to strict guidance and recommendations from national bodies. This study aimed to assess the performance and effectiveness of capsule-sponge assessment of long segment Barrett's Oesophagus. Method From September 2022 to June 2024, 379 patients received capsule-sponge assessment of their Barrett's Oesophagus using the CytospongeTM device. All patients were entered onto a prospectively maintained database and those with a previously identified long segment with no p53 positivity or atypia on initial sponge analysis were brought forward for endoscopic assessment at 12 months, rather than the current standard of 18 to 24 months. Endoscopy results were recorded and patients assessed for development of inter-test malignancy. Results 14 patients who had a Cytosponge (4%) were identified with a previously measured long-segment of Barrett's Oesophagus. The range of Prague Classification was C (6-12cm) M (6-13cm) and none of the patients had previously had dysplasia. All patients were offered surveillance endoscopy at 12 months. One patient refused endoscopy due to discomfort, though she did agree to continued capsule-sponge testing. Of the remaining 12 patients, all had successful endoscopy and Barrett's mapping. None had developed inter-test malignancy and all had persisting long segment Barrett's oesophagus. There were no other concerning findings at endoscopy. Conclusion Capsule sponge assessment of long segment Barrett's Oesophagus is safe and well tolerated. Patient feedback universally favoured capsule sponge over endoscopic assessment, particularly because of the increased length of time required for mapping of long segment disease. Poor tolerance of endoscopy led to refusal to have endoscopic surveillance in at least one patient in this series. By increasing frequency of capsule sponge assessment, even patients with long segment Barrett's Oesophagus may be suitable for regular surveillance without endoscopy.

The effectiveness of antidepressant therapy against anhedonia in patients with alcohol dependence

The article presents the results of a scientific study aimed at determining the effectiveness of the drug Vortioxetine (Brintellix) in the treatment of affective spectrum disorders in patients with alcohol dependence in a drug treatment hospital, since the drug is promising for widespread use in the drug therapy of a number of mental disorders and in the future could be included in the standard of medical care in the field of psychiatry-addictology. It is known that anhedonia is one of the mental disorders in withdrawal syndrome, which provokes relapses of an addictive disorder and negatively affects the duration and quality of remissions of patients with an addiction profile. At the same time, the study of antidepressant therapy in the treatment of alcohol dependence remains relevant, since poor tolerance, side effects, and deterioration of the patient's general condition may affect adherence to drug therapy. In the present study, anhedonia was assessed on the Snaith-Hamilton SHAPS scale, anxiety-depressive manifestations using the HADS hospital anxiety and depression scale and quality of life according to the SF-36 questionnaire during 24 weeks of follow-up.The result of drug therapy with Vortioxetine was the relief of affective disorders in alcohol dependence, which contributed to the improvement of overall subjective well-being, the degree of satisfaction with the quality of life and a decrease in anxiety-depressive tendencies and anhedonia. In addition, minimal and minor adverse reactions when taking Vortioxetine affected the increased adherence of the examined patients to medical prescriptions and recommendations.Conclusions. The use of Vortioxetine in the treatment of affective disorders among patients suffering from alcohol dependence provides new opportunities to help people suffering from alcohol addiction. Vortioxetine can be recommended both at the stage of inpatient care and outpatient treatment, since when it was taken, stable positive dynamics of antidepressant, anti-anxiety and antiangedonic effects were recorded.

Semaglutide Ameliorates Diabetic Neuropathic Pain by Inhibiting Neuroinflammation in the Spinal Cord

Glucagon-like peptide 1 (GLP-1) receptor agonists are frequently used to treat type 2 diabetes and obesity. Despite the development of several drugs for neuropathic pain management, their poor efficacy, tolerance, addiction potential, and side effects limit their usage. Teneligliptin, a DPP-4 inhibitor, has been shown to reduce spinal astrocyte activation and neuropathic pain caused by partial sciatic nerve transection. Additionally, we showed its capacity to improve the analgesic effects of morphine and reduce analgesic tolerance. Recent studies indicate that GLP-1 synthesized in the brain activates GLP-1 receptor signaling pathways, essential for neuroprotection and anti-inflammatory effects. Multiple in vitro and in vivo studies using preclinical models of neurodegenerative disorders have shown the anti-inflammatory properties associated with glucagon-like peptide-1 receptor (GLP-1R) activation. This study aimed to investigate the mechanism of antinociception and the effects of the GLP-1 agonist semaglutide (SEMA) on diabetic neuropathic pain in diabetic rats. Methods: Male Wistar rats, each weighing between 300 and 350 g, were categorized into four groups: one non-diabetic sham group and three diabetic groups. The diabetic group received a single intraperitoneal injection of streptozotocin (STZ) at a dosage of 60 mg/kg to induce diabetic neuropathy. After 4 weeks of STZ injection, one diabetic group was given saline (vehicle), and the other two were treated with either 1× SEMA (1.44 mg/kg, orally) or 2× SEMA (2.88 mg/kg, orally). Following a 4-week course of oral drug treatment, behavioral, biochemical, and immunohistochemical analyses were carried out. The mechanical allodynia, thermal hyperalgesia, blood glucose, advanced glycation end products (AGEs), plasma HbA1C, and spinal inflammatory markers were evaluated. Results: SEMA treatment significantly reduced both allodynia and hyperalgesia in the diabetic group. SEMA therapy had a limited impact on body weight restoration and blood glucose reduction. In diabetic rats, SEMA lowered the amounts of pro-inflammatory cytokines in the spinal cord and dorsal horn. It also lowered the activation of microglia and astrocytes in the dorsal horn. SEMA significantly reduced HbA1c and AGE levels in diabetic rats compared to the sham control group. Conclusions: These results indicate SEMA’s neuroprotective benefits against diabetic neuropathic pain, most likely by reducing inflammation and oxidative stress by inhibiting astrocyte and microglial activity. Our findings suggest that we can repurpose GLP-1 agonists as potent anti-hyperalgesic and anti-inflammatory drugs to treat neuropathic pain without serious side effects.

Clinical outcomes in patients in any phase of CML treated with ponatinib in France-Data from the TOPASE observational study.

The TOPASE study was set up to evaluate the outcomes of chronic myeloid leukaemia [CML] patients treated with ponatinib (PON) in a real-world setting in France. One hundred and twenty CML patients, 105 in chronic phase (CP), 8 in accelerated phase (AP) and 7 in blastic phase (BP) were included. Fifty-one (49%) of the CP-CML patients were in third line of treatment. The trigger for PON initiation in CP-CML was 'poor response' in 67 patients, 'poor tolerance' in 28 patients and 'response enhancement' in seven patients. The median dose at initiation was 30 mg/day [Q1; Q3 = 15; 30] in CP-CML and 45 mg/day [Q1; Q3 = 30; 45] in AP/BP-CML. Of 98 CP-CML evaluable patients, 72 (73.5%) were considered as responders (MMR) at one time point at least once, especially for those in second line of treatment and/or presenting a T315I mutation. Ninety-six of 120 (80%) patients reported at least one adverse event. An arterial occlusive event (AOE) was reported in 11 patients (9.2%). Thus, these real-life data confirm the potency of ponatinib in resistant or intolerant patients with an acceptable safety profile in non-selected patients. NCT number: NCT04048564.

Early intravenous branched-chain amino acid-enriched nutrition supplementation in older patients undergoing gastric surgery: a randomized clinical trial

BackgroundThe initiation time and formula for supplemental parenteral nutrition after surgery require optimization, especially in older patients undergoing major gastrointestinal surgery. This study aimed to assess the effect of early supplementation with a branched-chain amino acid (BCAA)-enriched formula (BAF) on short-term postoperative outcomes in older patients undergoing gastric surgery.MethodsThis single-center, prospective, double-blinded, randomized clinical trial was conducted from March 10, 2020, to September 15, 2022. Patients aged 65–80 years with gastric cancer scheduled for curative resection were assessed for eligibility and randomly allocated to a high-proportion BCAA (HBCAA) (early supplementation with the BAF) or control (routine nutrition) group. The primary outcome was the standardized length of hospital stay (LOS).ResultsA total of 150 patients were randomized. Thirteen patients were excluded due to the resection of other organs, presence of metastasis, or withdrawal of consent. Finally, we included 70 and 67 patients in the HBCAA and control groups, respectively (mean age: 70.5 ± 4.2 years; 96 men [70.1%]). The standardized LOS was significantly shorter in the treatment group than in the control group (median [interquartile range]: 8.0 [7.8, 8.0] vs. 8.5 [8.0, 9.0] days; mean difference, 0.38; 95% confidence interval [CI], 0.02–0.74 days; P < .001). Patients in the HBCAA group showed better gastrointestinal function with faster defecation (4.0 [3.6, 5.0] vs. 5.0 [4.0, 5.5] days; mean difference, 0.6 days; 95% CI, 0.26–0.94 days; P < .001) and semi-liquid diet initiation (8.0 [7.5, 8.0] vs. 8.0 [8.0, 8.8] days; mean difference, 0.36 days; 95% CI, 0.03–0.7 days; P < .001) and had lesser weight loss at postoperative day 5 than those in the control group did (3.5 [2.7, 6.5] vs. 4.9 [3.3, 7.6]%; mean difference, 1.23%; 95% CI, 0.27–2.19%; P = .011).ConclusionsIn this randomized clinical trial, compared with routine nutrition, early supplementation with a BAF was associated with a shorter standardized LOS in older patients undergoing gastric surgery, suggesting that it may be a favorable strategy for patients with a poor tolerance to external nutrition who are undergoing major surgery.Trial registrationClinicalTrials.gov; Identifier: ChiCTR2000029635.

Chronic Hepatitis D Virus Infection and Its Treatment: A Narrative Review

More than 12 million individuals worldwide are chronically infected with the hepatitis D virus (HDV). HDV infection is the most severe form of viral hepatitis since it requires hepatitis B virus co-infection and accelerates progression to cirrhosis and hepatocellular carcinoma. Therefore, treatment modalities to slow the progression of the disease are essential but not yet available. In addition, no antiviral treatment to date has been shown to reliably eradicate HDV. Pegylated interferon (PEG-IFN) is the only universally used treatment to suppress HDV RNA replication and improve liver inflammation and fibrosis. This treatment can be completed in 12–18 months, but cure rates remain low, and success does not reliably increase with the addition of a nucleos(t)ide analog. PEG-IFN therapy is also limited by poor tolerability and multiple adverse effects, including neutropenia, thrombocytopenia, and neuropsychiatric symptoms. Newer antiviral therapies in development target unique aspects of HDV viral replication and show promising results in combination with PEG-IFN for long-term HDV RNA suppression. These newer antiviral therapies include buleviritide (which blocks HDV entry), lonafarnib (which prevents HDV assembly), and REP-2139 (which prevents HDV export). In this manuscript, we discuss the characteristics of HDV infection and review the new antiviral therapies approved for treatment and those under investigation.

Comparative analysis of the 2016 diastolic guidelines and left atrial stiffness in predicting exercise tolerance and cardiac events

Abstract Background While the 2016 ASE/EACVI guideline for diastolic dysfunction is a robust tool for prognostication, their complexity and 20% rate of indeterminate limit their routine clinical practice. Purpose Left atrial (LA) stiffness, calculated as the E/e' ratio divided by LA strain, provides a simpler measure that indirectly reflects LA pressure. This study aims to evaluate whether LA stiffness can be better than the 2016 guidelines in predicting poor exercise tolerance and cardiac events (cardiac death or heart failure hospitalization) in patients with dyspnea. Methods In this retrospective single-center cohort study, 404 patients who underwent echocardiography and cardiopulmonary exercise test simultaneously were reviewed. Poor exercise tolerance was defined by a peak oxygen uptake (VO2) of &amp;lt;14 ml/kg/min or a minute ventilation-carbon dioxide production (VE/VCO2) slope of ≥ 40. The predictive abilities of LA stiffness for peak VO2, VE/VCO2 slope, and cardiac outcomes (cardiac death or heart failure hospitalization) were compared to those of the 2016 guidelines using ROC curve analysis. Results The mean left ventricular ejection fraction was 50% (IQR 58.58-66.70). Of the 404 patients (mean age 58.51, male 50.74%), peak VO2 &amp;lt; 14 and VE/VCO2 ≥ 40 were observed in 38 and 24 patients, and cardiac events occurred in 37 patients during median follow up of 85.45 months. ROC analysis showed that LA stiffness had AUC values of 0.697 (95% CI: 0.604-0.789) for peak VO2 &amp;lt; 14, 0.645 (95% CI: 0.529-0.760) for VE/VCO2 slope ≥ 40, and 0.628 (95% CI: 0.541-0.715) for cardiac events. The 2016 guidelines achieved AUCs of 0.685 (95% CI: 0.604-0.766), 0.586 (95% CI: 0.481-0.690), and 0.589 (95% CI: 0.505-0.674). Statistical comparison revealed no significant difference between the predictive capabilities of LA stiffness and the 2016 guidelines (p-values: 0.735, 0.165, and 0.439, respectively). (Figure) Conclusion LA stiffness offers comparable diagnostic accuracy to the 2016 ASE/EACVI guidelines in assessing poor exercise tolerance and cardiac events in patients with dyspnea. Given its simplicity and ease of measurement, LA stiffness represents a viable alternative for evaluating diastolic dysfunction.ROC curve

Clinical evidence of pacemaker implantation during gestation: a case series

Abstract Background Although recommended avoid any intervention during gestation in cases of poor tolerance to high degree atrioventricular block, pacemaker implantation may be necessary in pregnant women. Purpose To present outcomes of pacemaker implantation during gestation. Methods This prospective, single center study included 10 cases of pacemaker implantation during gestation (median age of patient - 26 years old at 18 weeks of gestation). We evaluated the further course of gestation and obstetric outcomes after implantation in comparison with pregnant with tachyarrythmias (n=111). Results Among 121 pregnant women with varying arrhythmias high degree atrioventricular block was detected in 10 cases (8,3%). In 6 cases this bradyarrhythmia diagnosed for the first time in gestation (60%). All pregnant with high degree atrioventricular block had clinical signs: dizziness and weakness (100%), syncope (70%), episodes of low blood pressure (100%). Pacemaker implantation performed due to hemodynamic instability and poor tolerance of bradyarrhythmia in all cases. Using electroanatomical mapping (Ensite Precision system)and echocardiographic guidance helped to reduce fluoroscopy time. For one pregnant implanted leadless pacemaker (Micra) with achieved more than 80% atrio-ventricular synchronization. Outcomes: further course of gestation characterized by increased incidence of uterine contractile activity (30%) in cases of high degree atrioventricular block, that was significantly higher than in pregnant with tachyarrhythmias (2%) (p=0.007). There were no differences in the rate of other complication: uterine blood flow violation (20% vs 12%, p=0.520), placental abraption (10% vs 5%, p=0.237) and preeclampsia (10% vs 5%, p=0.237). Vaginal type of delivery was in the majority of cases in both groups (70% vs 86%, p=0.553). Neonatal outcomes characterized with normal range of fetal birth weight (median 3163 vs 3212 grams, p=0.981) and 5 minute Apgar score (median 8.6 vs 8.7, p=0.564). There was no incidence of maternal and fetal mortality. In 12 month follow-up all patient have optimal electrical parameters of devise and remained stable over time. Conclusions High degree atrioventricular block in pregnant characterized by increased rate of uterine contractile activity. Pacemaker implantation during gestation can be effectively performed and associated with benign outcomes.

Virologically suppressed switch to Dolutegravir/Lamivudine 2-Drug regimen versus switch to commonly prescribed 3-Drug regimens in the United States

BackgroundTwo-drug regimens (2DRs) have been introduced in recent years to potentially reduce antiretroviral therapy (ART) toxicities and drug-drug interactions while demonstrating comparable efficacy to three-drug regimens (3DRs) for people with HIV (PWH). The objective of this study was to compare the real-world effectiveness and durability of a single-tablet 2DR of dolutegravir/lamivudine (DTG/3TC) with that of commonly prescribed 3DRs in ART-experienced, virologically suppressed PWH during the first 24 months of DTG/3TC availability in the United States.MethodsVirologically suppressed (viral load [VL] < 200 copies/mL) adult PWH initiating DTG/3TC 2DR, bictegravir/emtricitabine/tenofovir alafenamide (BIC/FTC/TAF), or a DTG-based 3DR between 01MAY2019 and 31OCT2020 were identified in the OPERA® cohort and followed through 30APR2021. Univariate Poisson regression (incidence rates) and marginal structural Cox proportional hazards models with inverse probability of treatment weights (hazard ratios) were used to quantify relationships between regimen type and confirmed virologic failure (2 consecutive VLs ≥ 200 copies/mL) or regimen discontinuation. Reasons for discontinuation were examined.ResultsA total of 8,037 ART-experienced, virologically suppressed PWH met the inclusion criteria and switched to DTG/3TC (n = 1,450), BIC/FTC/TAF (n = 5,691), or a DTG-based 3DR (n = 896). Incidence rates of confirmed virologic failure were low for all groups, at 0.66 (DTG/3TC), 0.84 (BIC/FTC/TAF), and 1.78 (DTG 3DR) per 100 person-years (py). Compared to DTG/3TC, only the DTG 3DRs were associated with a statistically significant increased hazard of confirmed virologic failure (hazard ratio: 5.21, 95% confidence interval: 1.85, 14.67). Discontinuation rates per 100 py were highest in the DTG 3DR group (24.90), followed by the DTG/3TC group (17.69) and the BIC/FTC/TAF group (8.30). Regardless of regimen, discontinuations were infrequently attributed to effectiveness (VL ≥ 200 copies/mL; 4%) or tolerability (adverse diagnoses, side effects, or lab abnormalities; 6%).ConclusionsAmong virologically suppressed PWH initiating a new regimen, few individuals experienced virologic failure in real-world clinical care. While rates of regimen discontinuation were high, most discontinuations could not be attributed to a lack of virologic control or poor tolerability. These findings suggest that DTG/3TC is an effective option for ART-experienced, virologically suppressed PWH.

Late eating is associated with poor glucose tolerance, independent of body weight, fat mass, energy intake and diet composition in prediabetes or early onset type 2 diabetes

This study investigates the impact of habitual late calorie intake on glucose metabolism in adults with overweight or obesity and diet or metformin-controlled prediabetes or type 2 diabetes independently of body weight, fat mass, energy intake or diet composition. Participants (n = 26) were classified as Later Eaters (LE) if ≥45% daily calories were consumed after 5 pm and Early Eaters (EE) if not, based on daily caloric intake assessed over 2-wk. EE and LE did not differ in anthropometrics or daily energy intake, but LE consumed more carbohydrates (p = 0.038) and fats (p = 0.039) after 5 pm. Fasting glucose, insulin, and C-peptide did not differ between groups but LE exhibited higher glucose concentrations after an oral glucose tolerance test (p = 0.001), even after adjusting for body weight, fat mass, energy intake and diet composition (p < 0.05). Glucose results remained when participants with T2D were excluded (p = 0.031). After diabetes status adjustment, differences in glucose concentrations were higher in LE for time 30 (p = 0.028) and 60 min (p = 0.036). LE, compared to EE, had poorer glucose tolerance, independent of body weight, fat mass, daily energy intake and diet composition. ClinicalTrials.gov: NCT04465721.

Recent Progress on Organic Electron Donors (OEDs) Enabled Radical Reactions

Over the past few decades, organic transformations facilitated by small organic molecules have witnessed considerable advancements. Small organic molecules have been widely applied to the construction of various skeletons. However, reduction as one of the fundamental reactions is generally initiated by metal‐containing reducing agents, although the initial progress of organic electron donors (OEDs) enabled reductive cleavage of some chemical bonds had been achieved in 1990s. Due to their structural diversity and tunability, OEDs can overcome the limitations of metal‐based reducing agents, such as low selectivity and poor functional group tolerance as well as the environmental problems caused by substantial inorganic waste after reactions. Building on a brief historical overview of OED research, this review focuses on the rencent advancements of the OEDs promoted radical reactions. It covers the reduction of C‐X (X =C, O, N etc.) single bonds, radical cyclization, intermolecular radical addition to unsaturated bonds, radical coupling, functionalization of aromatics, and C‐H bond activation. Additionally, the mechanistic insights of the typical reactions are highlighted for well understanding of the reaction mode involving OEDs.

Poor Tolerability of Lenvatinib in Elderly Patients with Advanced Hepatocellular Carcinoma after Disease Progression following First-Line Atezolizumab Plus Bevacizumab: A Multicenter Study

Introduction: We investigated the effectiveness of lenvatinib (LEN) after disease progression following first-line treatment with atezolizumab plus bevacizumab (Atez/Bev) in patients with unresectable hepatocellular carcinoma (HCC). Methods: One hundred and ten HCC patients treated with Atez/Bev as first-line systemic chemotherapy were enrolled and underwent dynamic computerized tomography/magnetic resonance imaging to determine the treatment response. We evaluated the treatment efficacy and prognosis after second-line LEN treatment, especially in elderly patients. Results: Of the 110 study patients, 88 patients (80%) were determined to have progressive disease (PD) during the observation periods, and 40 patients received second-line LEN therapy. The 40 patients included 13 patients who were unable to continue LEN until the initial evaluation due to adverse events (AE). The 27 patients who were able to continue LEN therapy (Group A) were significantly younger at initiation of Atez/Bev than those who could not continue (71 vs. 77 years old, p = 0.013). Comparing the OS and PFS between Group A and 44 patients that included 13 patients who were unable to continue LEN and 31 patients did not receive the second-line treatment (Group B), the former had significantly better OS than Group B (31.1 vs. 17.8 months, p = 0.035). Conclusions: The tolerability of second-line LEN therapy was lower in elderly patients, and the OS from the start of Atez/Bev therapy was different depending on the tolerability of second-line LEN therapy.

The Role of Parenteral Nutrition in Cancer in Indian Settings

Background: Almost 50% of patients with cancer suffer from malnutrition during their first hospital visit. However, it is often overlooked and undiagnosed and is associated with morbidity, mortality, poor tolerance to treatment, and treatment outcomes. Guidelines recommend supportive nutrition from the early stages of cancer treatment. However, in clinical practice, nutritional support is often prescribed only as an end-of-life intervention or is not prescribed at all; moreover, the use of parenteral nutrition (PN) is not well-defined. There are limited practical guidelines on the use of PN in patients with cancer. Methods: A multidisciplinary group of specialists in India formulated this consensus to guide oncologists on the judicious use of PN in Indian settings. It includes general and cancer-specific recommendations on the use of PN, supplemental PN (SPN), composition of PN, and monitoring patients to prevent adverse events associated with PN. Recommendations: The risk of malnutrition should be assessed at the very first presentation of a patient with cancer. These patients’ nutritional requirements are largely like those of the healthy population. Nutritional assessment of all cancer patients should begin at diagnosis and repeated regularly to initiate and monitor early nutritional intervention, before the general status is severely compromised. Oncologists and nutritionists need to be educated about using the appropriate nutrition support options according to the guidelines. While EN should be the preferred form of nutritional support, in specific circumstances PN might be a better option. Early PN in specific settings provides additional benefits, and is particularly important in some types of cancers. SPN as an additional nutritional support to EN can improve treatment tolerability and quality-of-life of patients with cancer. Education is also necessary for awareness about preventing and managing adverse effects of PN, which is the major reason for poor adoption of PN.

Characteristics of patients with liver tumors deemed ineligible for enrollment on Children's Oncology Group trial AHEP1531: An opportunity to expand inclusion criteria and improve outcome.

Specific patients with hepatoblastoma (HB) and hepatocellular carcinoma (HCC) do not meet eligibility criteria for Children's Oncology Group (COG) trials, limiting an understanding of how comorbidities affect the outcome. We define such a population for future-focused care improvements. A questionnaire was sent to COG institutional principal investigators to obtain anonymized data regarding patients with a liver tumor diagnosis not enrolled on AHEP1531 due to ineligibility by trial criteria or other reasons (excluding parent/patient preference). Responses received for 55 patients (38 HB, 4 HCC, and 13 not reported) included 12 excluded from further analysis due to various factors, including lack of additional information. Five patients were eligible but not enrolled due to pandemic-related staffing issues (n=1) or the best interest of the patient (physician preference, n=1; risk for poor tolerance of chemotherapy, n=1; not specified, n=2). The remaining 38 patients included 1 ineligible due to a prior malignancy, 9 due to performance status, and 4 due to timing requirements. Thirty-five of 38 patients were ineligible due to organ function criteria (pulmonary/oxygen requirement, n=25; renal, n=10; liver, n=4; cardiac, n=3). Seven patients were ineligible due to two or more organ function criteria. Twenty-five of 38 patients were reported to have a preexisting condition including 4 patients with trisomy 18. Patients with HB, and potentially HCC, who are ineligible for COG trials are primarily patients with an oxygen requirement and/or renal insufficiency, often associated with preexisting congenital conditions. Such patients would benefit from future studies to improve outcomes.

Mediastinal Teratoma with Angiosarcomatous Overgrowth in a Background of Vasculogenic Mesenchymal Tumor

Abstract Introduction/Objective Vasculogenic mesenchymal tumor refers to neoplastic reiteration of embryonic vasculogenesis. It is most commonly associated with nonseminomatous germ cell tumors of the mediastinum, in particular yolk sac tumor. In rare instances these lesions progress to angiosarcoma. Herein, we describe a case of angiosarcoma in a background of vasculogenic mesenchymal tumor in the setting of a mediastinal teratoma. Methods/Case Report A 33-year-old male, with a past medical history of anxiety, and right orchiectomy for testicular torsion, presented with shortness of breath, chest pain, and left arm swelling. Imaging studies demonstrated a mediastinal mass. Biopsy of the mass showed a germ cell tumor most compatible with a teratoma in the limited specimen. The patient received two rounds of chemotherapy and additional treatments were discontinued due to poor tolerance. Subsequent imaging showed continued increase in the size along with mass effect causing moderate to severe compression of the superior vena cava. Subsequently, the patient underwent resection of the mass. Grossly the mass was predominantly encapsulated with areas of capsular disruption. Sectioning revealed heterogeneous cut surfaces with fleshy, cystic, and necrotic areas. Morphologically the tumor was composed predominantly of teratomatous elements with areas of anastomosing atypical vascular channels within a hypocellular stroma suggestive of vascular genic mesenchymal as well as areas reminiscent of Masson lesion. Focally within these areas were malignant spindle cell proliferations compatible with angiosarcoma. The patient had an elevated AFP; however, no yolk sac tumor component was identified after thorough sampling. Final diagnosis of teratoma with angiosarcoma in a background of vasculogenic mesenchymal tumor was rendered after expert consultation. Results (if a Case Study enter NA) NA Conclusion Somatic-type malignancy and sarcomatous overgrowth are known to occur in mediastinal germ cell tumors; however, classification of the sarcomatous overgrowth can be challenging. Vasculogenic mesenchymal tumor is an exceedingly rare sarcomatous overgrowth that can rarely progress to angiosarcoma.

Obesity Nephropathy: A Current Overview

The obesity pandemic is a public health problem that is evolving at high speed with both functional and vital outcomes. Recently, many studies have shown that obesity is a driver of chronic kidney disease onset and progression. The mechanisms underlying this fact are multiple including inflammation, oxidative stress, insuline resistance and hemodynamic change with inappropriate RAAS and SNS activation; occuring on a particularly genetic basis of individual predisposition. In this field, Obesity-related glomerulopathy is characterized by glomerulomegaly with localized and segmental glomerulosclerosis lesions. Main symptoms are non specific, dominated by microproteinuria, rarely nephrotic syndrome and a slowed decline in glomerular filtration rate. As for treatment, it starts essentially with lifestyle interventions targeting a meaningful and sustainable weight loss, accompanied by antiobesity medications (AOMS) including RAAS blockers, SGLT2inhibitors and since very recently, long-acting glucagon-like peptide-1 (GLP-1) receptor agonists (GLP-1 RA) which were shown to be effective in managing weight loss in non-chronic kidney disease (CKD) patients. Preliminary results of more definitive studies in CKD patients are currently being finalized. Bariatric surgery could reduce the risk of mortality in obese CKD patients; it is recommended for patients with severe morbid obesity, poor tolerance to AOMS, particularly GLP RA, or those whose long-term medication costs represent a barrier to sustainable results. In this review, we summarize epidemiological data on obesity nephropathy, its pathophysiological mechanisms, clinical features and perspectives on its treatment.

Isolation and Whole-genome analysis of Desmodesmus sp. SZ-1: Novel acid-tolerant carbon-fixing microalga

Utilizing microalgae to capture flue gas pollutants is an effective strategy for mitigating greenhouse gas emissions. However, existing carbon-fixing microalgae exhibit poor tolerance towards acidic flue gas. In this study, the Desmodesmus sp. SZ-1, which can thrive in acidic environments and efficiently sequester CO2, was isolated. Desmodesmus sp. SZ-1 exhibited strong acid tolerance ability, with an average carbon fixation rate of 497.6 mg/L/d under 10 % CO2 and pH 3.5. Physiological analysis revealed that SZ-1 responded to high CO2 by increasing chlorophyll levels while coping with acidic stress by activating antioxidant enzymes. Genome analysis revealed a large number of carbon fixation and acid adaptation genes, involved in membrane lipid biosynthesis, H+ pumps, molecular chaperones, peroxidase system, amino acid synthesis, and carbonic anhydrase. This study provides a novel algal resource for mitigating acid gas emissions and a comprehensive genetic database for genetically modifying microalgae.

Active suicidal ideation in an adolescent with autism spectrum disorder receiving methylphenidate: a case report

BackgroundMethylphenidate is a psychostimulant treatment widely prescribed in children and adolescents with attention deficit hyperactivity disorder. Although published studies are reassuring regarding the safety and tolerability of this treatment in the short and long term, there are case studies that have reported the possibility of serious adverse effects following methylphenidate initiation in children and adolescents.Case presentationIn the present study, we illustrate the case of a 13-year-old adolescent, who was diagnosed with autism spectrum disorder, attention deficit hyperactivity disorder, and other psychiatric comorbidities. The patient developed active suicidal ideation a few weeks after initiating methylphenidate. He also presented irritability accentuation, insomnia, decreased appetite, and an increase in temper tantrums after initiation of this treatment. Psychiatric evaluation, according to the Diagnostic and Statistical Manual of Mental Disorders (DSM-5), did not reveal major psychiatric disorders that could explain them, particularly mood disorders. The risk of suicide was assessed as high indicating a hospitalization and the immediate discontinuation of this treatment. The evolution was marked by a disappearance of suicidal thoughts 2 days after discontinuation of methylphenidate and a clear decrease in symptoms of poor tolerance. The authors were unable to establish a cause-and-effect link between the prescription of methylphenidate and the appearance of suicidal thoughts in this patient, but the results of studies already published seem to provide clues that could explain this link.ConclusionsThe purpose of this work is to alert clinicians to the possibility that young people who have multiple neurodevelopmental disorders may experience suicidal thoughts after starting methylphenidate even in the absence of mood disorders. The link between the prescription of this treatment and the onset of suicidal ideation is not as clear and requires more controlled studies. This suggests particular attention, such as informing the young people and their families beforehand and planning rigorous psychiatric evaluations after the prescription.

EPO modified MSCs protects SH-SY5Y cells against ischemia/hypoxia-induced apoptosis via REST-dependent epigenetic remodeling

Hypoxic-ischemic encephalopathy (HIE) is a diffuse brain tissue injury caused by acute ischemia and hypoxia, and it is most commonly found in newborn infants but can also occur in adults. Mesenchymal stem cell (MSC) therapies have showed improved outcomes for treating HIE-induced neuronal defects. However, many key issues associated with poor cell viability and tolerance of grafted MSCs after HIE remain to be resolved. Genetic engineering could endow MSCs with more robust regenerative capacities. Our research, along with that of other scientists, has found that the expression of intracellular erythropoietin (EPO) in human umbilical cord MSCs (hUC-MSCs) increases proportionally with the duration of hypoxia exposure. Furthermore, we observed that EPO, when introduced into the EPO gene-modified hUC-MSCs, can be secreted into the extracellular space. However, the underlying mechanisms that support the neuroprotective effects of EPO-MSCs remain unclear. EPO-MSCs, hUC-MSCs, and NC-MSCs were identified by flow cytometry, osteogenic, and adipogenic differentiation assays. The oxygen-glucose deprivation (OGD)-induced SH-SY5Y cell-line was established, and five groups were set up: control, 24-h ischemia-hypoxia, co-cultured with hUC-MSCs, NC-MSCs, and EPO-MSCs after hypoxia. LEGENDplex™ multi-factor flow cytometry was used to detect the secretion of inflammatory factors in cell supernatants and cerebrospinal fluid. Chromosome-targeted excision and tagging (CUT&Tag) sequencing was applied to detect genomic H3K4me2 modifications, and conjoint analysis with transcriptome sequencing (RNA-seq) was performed. Lentiviral vector infection was used to construct SH-SY5Y cells with stable knockdown of RE1-silencing transcription factor (REST), and flow cytometry was used to detect alterations in apoptosis. Finally, the molecular mechanism underlying the neuroprotective and anti-apoptotic effects of EPO-MSCs was investigated using RNA sequencing, qRT-PCR, and western blot assays. Our results suggest that EPO-MSCs are genetically engineered to secrete significantly more EPO. EPO-MSCs treatment has anti-apoptotic properties and offers neuronal protection during ischemic-hypoxic injury. Furthermore, RNA-seq results suggest that multiple inflammation-related genes were down-regulated after EPO-MSCs treatment. Application of RNA-seq and CUT&Tag combined analysis found that the expressions of REST were significantly up-regulated. Lentiviral vector infection to construct REST knockdown SH-SY5Y failed to rescue apoptosis after hypoxia and co-culture with EPO-MSCs, and SETD2-mediated H3K36me3 protein level expression was reduced. EPO-MSCs may promote neuronal survival by affecting H3K4me2 and thus activating the expression of REST and TET3. EPO-MSCs also upregulated the modification level of SETD2-mediated H3K36me3 and regulated the expression of inflammation-related genes such as PLCG2, as well as apoptosis genes BCL2A1. To investigate the neuroprotective effects of EPO-modified hUC-MSCs and the underlying epigenetic regulatory mechanisms, this study aims to provide a theoretical foundation for the potential application of EPO gene-modified hUC-MSCs in the treatment of HIE.

7888 Mitotane Induces Different Modes Of Cell Death In Treatment Resistant And Sensitive Models Of Adrenocortical Carcinoma

Abstract Disclosure: S. Feely: None. N. Mullen: None. C. Hong: None. C. Hantel: None. W.E. Rainey: None. M.C. Dennedy: None. Adrenocortical carcinoma (ACC) is a rare aggressive cancer with poor survival. Adjuvant mitotane is the only approved drug for treatment of ACC. It improves survival but its use is limited by poor tolerability and drug resistance. For metastatic ACC, combination chemotherapy, using mitotane and etoposide, doxorubicin, and cisplatin improves survival, but efficacy is limited. Better understating the cytotoxic mechanisms of mitotane offers potential to develop improved therapeutic options for ACC. To investigate the underlying mechanisms in vitro, human ACC cells (HAC15 and H295R), in monolayer cell culture were treated with increasing concentrations of mitotane. Cell death was evaluated at 6 and 24 hours using flow cytometry analysis of Annexin V and Sytox Blue. This was complemented by Incucyte ® Live-Cell Analysis System imaging of annexin V and Sytox Blue staining. Expression of the markers of apoptosis, cleaved caspase 3, and necroptosis, phosphorylated MLKL and RIPK1 was measured at 6 and 24 hours. Mitotane significantly reduced the viability of H295R cells at 6 and 24 hours at the therapeutic concentration of 50uM (p&amp;gt;0.0001), thereby demonstrating treatment-sensitivity. In HAC15 cells, a supratherapeutic dose of 200uM was needed to significantly reduce viability (p&amp;gt;0.05) at 24 hours, indicating resistance to mitotane treatment at therapeutic concentrations. There was increasing Annexin V fluorescence with increasing mitotane concentration in H295R and HAC15 cells ar 6 and 24 hours without higher coinciding staining with Sytox Blue. Video analysis demonstrated these findings. Cleaved caspase 3 expression was associated with mitotane-induced cell death in H295R cells at 6 and 24 hours, indicating apoptosis. HAC15 cells demonstrated cleaved caspase 3 expression only at the highest concentration of mitotane exposure (600uM) at 6 hours, without appreciable expression at 24 hours. Phosphorylated-MLKL and RIPK1 expression was seen in controls and all mitotane doses in both cell lines at both timepoints, indicating necroptosis. In this study, H295R cells, representing a treatment-sensitive model of Mitotane undergo both apoptotic and necroptotic cell death at 6 and 24 hours of mitotane exposure. In contrast, HAC15 cells, demonstrated relative treatment resistance to mitotane, and undergo necroptotic cell death only. These results highlight the importance of understanding and targeting non-apoptotic and necroptotic cell death pathways, particularly when evaluating mechanisms of treatment resistance in ACC. Given the difference in the mechanism of cell death in treatment-sensitive and treatment-resistant cells, further exploration of necroptosis is necessary to better understand how ACC cells may manifest treatment resistance. Presentation: 6/1/2024