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1.
Pediatr Cardiol ; 2024 Aug 02.
Article in English | MEDLINE | ID: mdl-39093353

ABSTRACT

In this review we provide a brief description of recently published articles addressing topics relevant to pediatric cardiologists. Our hope is to provide a summary of the latest articles published recently in other journals in our field. The articles address: 1- The use of AI in fetal echocardiography, 2- The role of Apixaban in thromboembolism prevention in pediatric congenital heart disease, 3- Cardiovascular events in childhood cancer survivors, and lastly 4- the new consensus statement on cardiac catheterization for pediatrics and adults with congenital heart disease.

2.
Pediatr Cardiol ; 2024 Aug 01.
Article in English | MEDLINE | ID: mdl-39088090

ABSTRACT

The cone operation has revolutionized care for patients with Ebstein anomaly; however, acute post-operative right ventricular dysfunction (RVD) is common in this patient population. A single-center, retrospective review of 28 patients with Ebstein anomaly who underwent cardiac MRI (CMR) prior to cone reconstruction of the tricuspid valve was conducted. Measurements of atrial and ventricular size/function were assessed. Post-operative RVD was defined as the presence of moderate or severe systolic dysfunction on discharge echo. A two-tail t test was employed to compare the two groups. The average age at operation was 21.4 years (range 1.6-57.8) and 14 (50%) had RVD at discharge. Patients with post-operative RVD had significantly larger pre-operative right atrial (RA) maximum volume (p = 0.016) and RA minimum volume (p = 0.030). Patients with RVD had smaller pre-operative left atrial (LA) minimum volume (p = 0.012). Larger pre-operative right ventricular (RV) end-systolic volume (p = 0.046), lower RV ejection fraction (0.029), and smaller left ventricular (LV) end-diastolic volume (p = 0.049) were significantly associated with post-operative RVD. Post-operative RVD was associated with longer milrinone duration (p = 0.009) and higher maximum milrinone dose (p = 0.005) but was not associated with intensive care or hospital length of stay (p = 0.19 and 0.67, respectively). Increased RA and RV dilation and decreased LA and LV volumes are associated with the development of post-operative RVD following cone operation for Ebstein anomaly. Post-operative RVD affects milrinone dose and duration but is not associated with increased length of stay.

3.
Pediatr Cardiol ; 2024 Jul 20.
Article in English | MEDLINE | ID: mdl-39033244

ABSTRACT

Ebstein Anomaly (EA) is a malformation of the right heart, but there is data to suggest that the left ventricle (LV) can suffer from intrinsic structural and functional abnormalities which affect surgical outcomes. The LV in patients with EA is hypertrabeculated with abnormalities in LV function and strain. In this retrospective single-center study, patients with EA who underwent pre-operative cardiac MRI (CMR) between the periods of 2014-2024 were included along with a group of healthy-age-matched controls. Left ventricular and right ventricular volume, function and strain analyses were performed on standard SSFP imaging. LV noncompacted: compacted (NC/C) ratio and the displacement index of the tricuspid valve were measured. Forty-seven EA patients were included with mean age of 21.0 ± 17.6 years. Seventeen EA patients (36%) had mild pre-operative LV dysfunction on CMR and 1 (2.1%) had moderate LV dysfunction. Out of these 18 patients with LV dysfunction, only 2 were detected to have dysfunction on Echocardiogram. The global circumferential and longitudinal strain were significantly lower in the reduced LVEF group compared to those with preserved LVEF (- 14.8% vs. - 17%, p = 0.02 and - 11.9% vs. - 15.0%; p = 0.05; respectively) on CMR. A single EA patient met criteria for LVNC with a maximal NC/C ratio > 2.3. There was no statistically significant difference in NC/C ratio in the EA population (1.4 ± 0.6) vs. controls (1.1 ± 0.2), p = 0.17. There was an inverse correlation of LV ejection fraction with right ventricular end-diastolic volume and displacement index. All patients underwent the Da Silva Cone procedure at our center. Patients with preoperative LV dysfunction had longer duration of epinephrine use in the immediate postoperative period (33.7 ± 21.4 vs 10.2 ± 25.6 h, p = 0.02) and longer length of hospital stay (6.3 ± 3.2 vs 4.4 ± 1.2 days, p = 0.01). This is the largest study to date to evaluate preoperative LV structure and function in EA patients by CMR. In this cohort of 47 patients, preoperative LV dysfunction is fairly common and CMR has high sensitivity in detecting LV dysfunction as compared to Echo. True LV non-compaction was rare in this cohort. The presence of LV dysfunction is relevant to perioperative management and further study with larger cohorts and longer follow up are necessary.

5.
Acad Pediatr ; 2024 Jul 01.
Article in English | MEDLINE | ID: mdl-38959997

ABSTRACT

OBJECTIVE: Children of caregivers with limited health literacy are at risk of poorer health outcomes. Thus, health literacy-informed communication tools are critical to achieving a more equitable health system. However, there is no agreement on the health literacy skills pediatric residents should attain. We used Delphi methodology to establish consensus on health literacy objectives to inform development of a pediatric resident curriculum. METHODS: Our Delphi panel participated in three rounds of anonymous surveys to rank the importance of health literacy objectives in pediatric resident education. Consensus was defined as ≥70% of panelists identifying an objective as essential or 100% agreeing an objective was recommended or essential. RESULTS: Thirteen pediatric health literacy experts comprised a racially, geographically, and professionally-diverse panel. After three survey rounds, 27 of the initial 65 objectives met consensus. All final objectives aligned with Accreditation Council for Graduate Medical Education (ACGME) core competencies. CONCLUSIONS: A panel of pediatric health literacy experts established consensus on health literacy objectives specific to pediatric resident training. These prioritized objectives align with ACGME core competencies, as well as evidence-based strategies like teach-back, and newer considerations like addressing organizational health literacy. They should inform future health literacy curricula and assessment within pediatric residency programs.

6.
Alzheimers Dement (Amst) ; 16(3): e12614, 2024.
Article in English | MEDLINE | ID: mdl-38966621

ABSTRACT

INTRODUCTION: Alzheimer's disease (AD) blood biomarkers show promise for clinical diagnosis but their reliability in chronic kidney disease (CKD) is debated. This study investigates the impact of kidney transplant (KT) on AD biomarkers in CKD. METHODS: We assessed AD biomarkers in 46 CKD patients pre-KT, at 12 weeks and 12 months post-KT, with baseline measures from 13 non-CKD controls. Using linear mixed models, we examined associations with participant groups, estimated glomerular filtration rate (eGFR) and cognition. RESULTS: CKD patients showed elevated levels of neurofilament light (117 ± 72 vs. 11 ± 5 pg/mL), phosphorylated tau 181 (75 ± 42 vs. 13 ± 8 pg/mL), glial fibrillary acidic protein (193 ± 127 vs. 94 ± 39 pg/mL), amyloid ß 42 (17 ± 5 vs. 5 ± 1 pg/mL), and amyloid ß 40 (259 ± 96 vs. 72 ± 17 pg/mL) compared to controls. Post-KT, biomarker levels approached normal with improved eGFR, paralleled by enhanced cognitive function. DISCUSSION: AD blood biomarker elevations in CKD are reversible with improved kidney function through KT. Highlights: AD biomarker levels are extremely high in severe CKD.AD biomarker levels are higher in patients with kidney failure on dialysis when compared to CKD patients not on dialysis.These elevations in AD biomarker levels in kidney failure are reversable and decrease dramatically after kidney transplantation.The change in biomarker levels after transplantation align with changes in kidney function.The change in biomarker levels after transplantation align with changes in cognitive function.

7.
J Infect Dis ; 230(1): 15-27, 2024 Jul 25.
Article in English | MEDLINE | ID: mdl-39052709

ABSTRACT

Patients with B-cell lymphomas have altered cellular components of vaccine responses due to malignancy and therapy, and the optimal timing of vaccination relative to therapy remains unknown. Severe acute respiratory syndrome coronavirus 2 vaccines created an opportunity for new insights in vaccine timing because patients were challenged with a novel antigen across multiple phases of treatment. We studied serologic messenger RNA vaccine response in retrospective and prospective cohorts with lymphoma and chronic lymphocytic leukemia, paired with clinical and research immune parameters. Reduced serologic response was observed more frequently during active treatment, but nonresponse was also common within observation and posttreatment groups. Total immunoglobulin A and immunoglobulin M correlated with successful vaccine response. In individuals treated with anti-CD19-directed chimeric antigen receptor-modified T cells, nonresponse was associated with reduced B and T follicular helper cells. Predictors of vaccine response varied by disease and therapeutic group, and therefore further studies of immune health during and after cancer therapies are needed to individualize vaccine timing.


Subject(s)
COVID-19 Vaccines , COVID-19 , Leukemia, Lymphocytic, Chronic, B-Cell , Humans , Leukemia, Lymphocytic, Chronic, B-Cell/immunology , Leukemia, Lymphocytic, Chronic, B-Cell/therapy , Male , Female , Middle Aged , Aged , COVID-19 Vaccines/immunology , COVID-19 Vaccines/administration & dosage , Retrospective Studies , COVID-19/immunology , COVID-19/prevention & control , Prospective Studies , SARS-CoV-2/immunology , Adult , Antibodies, Viral/blood , Antibodies, Viral/immunology , Vaccination , Immunoglobulin M/blood , Lymphoma/immunology , Lymphoma/therapy , Aged, 80 and over
8.
BMC Womens Health ; 24(1): 431, 2024 Jul 27.
Article in English | MEDLINE | ID: mdl-39068405

ABSTRACT

BACKGROUND: While assisted reproductive technologies (ART) have helped many people experiencing infertility become pregnant, the ART process can take a psychological toll. This study examined whether and how perceived stress- and depression-related symptoms vary among individuals at different stages of the infertility and ART process, and whether ART-specific stressors and emotional support are associated with mental health symptomatology. METHODS: Data were collected using an online REDCap survey administered between July 2021 and March 2022. The survey was administered to 240 participants who had experienced infertility, including those who had not yet accessed ART, those undergoing ART but who were not yet pregnant, those currently pregnant through ART, and those who had given birth in the last year through ART. Each participant completed the Cohen Perceived Stress Scale (range 0-40) and the Edinburgh Depression Scale (range 0-30). Participants who had undergone ART were asked about their experience of ART-specific stressors and how helpful partner and provider support had been during the ART process. Survey data were analyzed using ANOVA and multivariate linear regressions. RESULTS: 88% of participants reported medium or high levels of perceived stress, and 43.8% of respondents showed probable indications of depression. Perceived stress and depression symptoms were significantly higher for individuals currently undergoing, but not yet pregnant from, ART treatments. These effect sizes were substantial; for example, depression scores in this group were five points higher than among currently pregnant individuals and nine points higher than among postpartum individuals. For the subset of participants who had used or were currently undergoing ART (N = 221), perceived social stigma and the physical and time demands of ART were significantly associated with higher stress and depression symptoms, while partner emotional support was associated with lower perceived stress. CONCLUSIONS: The ART process exacerbates perceived stress and depression symptoms among individuals experiencing infertility. Given the potential long-term impacts on both parent and child wellbeing, clinicians and policymaking groups, including the American Society for Reproductive Medicine (ASRM), should consider making access to mental health services a standard of care during infertility treatment.


Subject(s)
Depression , Reproductive Techniques, Assisted , Social Support , Stress, Psychological , Humans , Reproductive Techniques, Assisted/psychology , Female , Stress, Psychological/psychology , Adult , Depression/psychology , Pregnancy , Surveys and Questionnaires , Male , Infertility/psychology , Middle Aged , Young Adult
9.
Gynecol Oncol ; 189: 90-97, 2024 Jul 27.
Article in English | MEDLINE | ID: mdl-39068739

ABSTRACT

OBJECTIVE: Folate receptor alpha (FRα) is overexpressed on >90% of high-grade epithelial ovarian cancers (EOC). Targeting FRα with antibody-drug conjugates has proven utility in the platinum-resistant setting. It is also a potential therapeutic target for immuno-oncologic agents, such as peptide vaccines that work primarily via adaptive and humoral immunity. We tested the hypothesis that FRα peptide immunization could improve outcomes in patients with EOC following response to platinum-based therapy. METHODS: We conducted a randomized, double-blind, multicenter, phase II study to evaluate the safety and efficacy of TPIV200 (a multi-epitope FRα peptide vaccine admixed with GM-CSF) versus GM-CSF alone in 120 women who did not have disease progression after at least 4 cycles of first-line platinum-based therapy. Patients were vaccinated intradermally once every 4 weeks up to 6 times, followed by a boosting period of 6 vaccinations at 12-week intervals. Primary endpoints included safety, tolerability, and progression free survival (PFS). RESULTS: At study termination with a median follow-up of 15.2 months (range 1.2-28.4 months), 68 of 119 intention-to-treat patients had disease progression (55% in TPIV200 + GM-CSF arm and 59% in GM-CSF alone arm). The median PFS was 11.1 months (95% CI 8.3-16.6 months) with no significant difference between the treatment groups (10.9 months with TPIV200 + GM-CSF versus 11.1 months with GM-CSF, HR, 0.85; upper 90% CI 1.17]. No patient experienced a ≥ grade 3 drug-related adverse event. CONCLUSION: TPIV200 was well tolerated but was not associated with improved PFS. Additional studies are required to uncover potential synergies using multiepitope vaccines targeting FRα. Trial Registration NLM/NCBI Registry, NCT02978222, https://clinicaltrials.gov/search?term=NCT02978222.

10.
Cureus ; 16(5): e59724, 2024 May.
Article in English | MEDLINE | ID: mdl-38840994

ABSTRACT

This case report presents the successful management of a four-year-old male patient with pain in the lower right back tooth region. Clinical and radiographic examinations revealed the necessity for extraction of tooth 85 due to persistent infection and bone resorption, necessitating space maintenance. A modified distal shoe space maintainer, incorporating horizontal loops for enhanced adjustability, was utilized postextraction. The appliance was fabricated, cemented, and monitored through follow-up visits. At the 24-month recall, the permanent mandibular first molar (tooth 46) was clinically visible, indicating successful space maintenance. Incorporating horizontal loops into the distal shoe space maintainer represents an innovative approach in pediatric dentistry, offering clinicians a versatile tool for managing space loss and promoting optimal eruptive patterns.

11.
J Public Health Manag Pract ; 30(4): 593-596, 2024.
Article in English | MEDLINE | ID: mdl-38743201

ABSTRACT

Equitable social determinants of health (SDOH) screening has been recommended by the Centers for Medicare & Medicaid Services and the Joint Commission; however, little is known about Spanish-speaking caregiver preferences on how they would like to be screened. We conducted a cross-sectional study at 3 pediatric clinics (October-December 2019). Caregivers completed (in English or Spanish) an SDOH screening preferences survey. Three hundred eighty-two of 443 caregivers approached (response rate = 86.2%) completed the survey. Most were female, preferred Spanish, and completed only high school. Spanish-speaking caregivers had greater odds of preferring verbal SDOH screening (odds ratio: 4.1; 95% confidence interval, 1.8-9.2) than English-speaking caregivers. Verbal SDOH screening should be a consideration in families who speak Spanish. Future studies should utilize qualitative methods to further explore Spanish-speaking caregiver preferences for SDOH screening.


Subject(s)
Caregivers , Hispanic or Latino , Mass Screening , Social Determinants of Health , Humans , Female , Male , Caregivers/psychology , Caregivers/statistics & numerical data , Social Determinants of Health/statistics & numerical data , Cross-Sectional Studies , Surveys and Questionnaires , Mass Screening/statistics & numerical data , Mass Screening/methods , Mass Screening/psychology , Hispanic or Latino/statistics & numerical data , Hispanic or Latino/psychology , Adult , Middle Aged
12.
Sci Adv ; 10(22): eadl5576, 2024 05 31.
Article in English | MEDLINE | ID: mdl-38820163

ABSTRACT

Despite great progress in the field, chronic Pseudomonas aeruginosa (Pa) infections remain a major cause of mortality in patients with cystic fibrosis (pwCF), necessitating treatment with antibiotics. Pf is a filamentous bacteriophage produced by Pa and acts as a structural element in Pa biofilms. Pf presence has been associated with antibiotic resistance and poor outcomes in pwCF, although the underlying mechanisms are unclear. We have investigated how Pf and sputum biopolymers impede antibiotic diffusion using pwCF sputum and fluorescent recovery after photobleaching. We demonstrate that tobramycin interacts with Pf and sputum polymers through electrostatic interactions. We also developed a set of mathematical models to analyze the complex observations. Our analysis suggests that Pf in sputum reduces the diffusion of charged antibiotics due to a greater binding constant associated with organized liquid crystalline structures formed between Pf and sputum polymers. This study provides insights into antibiotic tolerance mechanisms in chronic Pa infections and may offer potential strategies for novel therapeutic approaches.


Subject(s)
Anti-Bacterial Agents , Pseudomonas aeruginosa , Sputum , Static Electricity , Sputum/microbiology , Anti-Bacterial Agents/pharmacology , Pseudomonas aeruginosa/drug effects , Pseudomonas aeruginosa/virology , Humans , Cystic Fibrosis/metabolism , Pseudomonas Infections/drug therapy , Pseudomonas Infections/microbiology , Tobramycin/pharmacology , Diffusion , Biofilms/drug effects , Bacteriophages
13.
Cureus ; 16(4): e58170, 2024 Apr.
Article in English | MEDLINE | ID: mdl-38741840

ABSTRACT

This comprehensive review delves into the intricate relationship between evolving dietary trends in preschoolers and the prevalence of early childhood caries (ECC). The investigation meticulously analyzes ECC epidemiology, etiology, and preventive strategies. The review unveils the multifaceted nature of ECC, highlighting microbial, dietary, and environmental factors contributing to its development. Significantly, the study explores the global prevalence of ECC and its substantial implications for the overall health, nutrition, and development of preschool-aged children. The implications for public health and policy are deliberated, advocating for targeted interventions and collaborative efforts among healthcare professionals, policymakers, educators, and parents. The conclusion presents a compelling call to action, urging collective engagement to mitigate the impact of ECC and prioritize the well-being of preschoolers. This review offers valuable insights for healthcare professionals, policymakers, educators, and parents to inform evidence-based strategies for addressing ECC and promoting early childhood oral health.

14.
Transplant Cell Ther ; 30(8): 810.e1-810.e16, 2024 Aug.
Article in English | MEDLINE | ID: mdl-38768907

ABSTRACT

In αß T-cell/CD19 B-cell depleted hematopoietic stem cell transplantation (αßhaplo-HSCT) recipients, antithymocyte globulin (ATG; Thymoglobulin) is used for preventing graft rejection and graft-versus-host disease (GVHD). The optimal dosing remains to be established, however. Here we present the first comparative analysis of 3 different ATG dosing strategies and their impact on immune reconstitution and GVHD. Our study aimed to evaluate the effects of 3 distinct dosing strategies of ATG on engraftment success, αß+ and γδ+ T cell immune reconstitution, and the incidence and severity of acute GVHD in recipients of αßhaplo-HSCT. This comparative analysis included 3 cohorts of pediatric patients with malignant (n = 36) or nonmalignant (n = 8) disease. Cohorts 1 and 2 were given fixed ATG doses, whereas cohort 3 received doses via a new nomogram, based on absolute lymphocyte count (ALC) and body weight (BW). Cohort 3 showed a 0% incidence of day 100 grade II-IV acute GVHD, compared to 48% in cohort 1 and 27% in cohort 2. Furthermore, cohort 3 (the ALC/BW-based cohort) had a significant increase in CD4+ and CD8+ naïve T cells by day 90 (P = .04 and .03, respectively). Additionally, we found that the reconstitution and maturation of γδ+ T cells post-HSCT was not impacted across all 3 cohorts. Cumulative ATG exposure in all cohorts was lower than previously reported in T cell-replete settings, with a lower pre-HSCT exposure (<40 AU*day/mL) correlating with engraftment failure (P = .007). Conversely, a post-HSCT ATG exposure of 10 to 15 AU*day/mL was optimal for improving day 100 CD4+ (P = .058) and CD8+ (P = .03) immune reconstitution without increasing the risk of relapse or nonrelapse mortality. This study represents the first comparative analysis of ATG exposure in αßhaplo-HSCT recipients. Our findings indicate that (1) a 1- to 2-fold ATG to ATLG bioequivalence is more effective than previously established standards, and (2) ATG exposure post-HSCT does not adversely affect γδ+ T cell immune reconstitution. Furthermore, a model-based ATG dosing strategy effectively reduces graft rejection and day 100 acute GVHD while also promoting early CD4+/CD8+ immune reconstitution. These insights suggest that further optimization, including more distal administration of higher ATG doses within an ALC/BW-based strategy, will yield even greater improvements in outcomes.


Subject(s)
Antilymphocyte Serum , Graft vs Host Disease , Hematopoietic Stem Cell Transplantation , T-Lymphocytes , Graft vs Host Disease/prevention & control , Antilymphocyte Serum/therapeutic use , Antilymphocyte Serum/administration & dosage , Humans , Hematopoietic Stem Cell Transplantation/adverse effects , Hematopoietic Stem Cell Transplantation/methods , Child , Male , Female , Adolescent , Child, Preschool , T-Lymphocytes/immunology , T-Lymphocytes/drug effects , Acute Disease , Infant , Receptors, Antigen, T-Cell, alpha-beta/metabolism
15.
J Neurodev Disord ; 16(1): 17, 2024 Apr 17.
Article in English | MEDLINE | ID: mdl-38632549

ABSTRACT

Monogenic disorders account for a large proportion of population-attributable risk for neurodevelopmental disabilities. However, the data necessary to infer a causal relationship between a given genetic variant and a particular neurodevelopmental disorder is often lacking. Recognizing this scientific roadblock, 13 Intellectual and Developmental Disabilities Research Centers (IDDRCs) formed a consortium to create the Brain Gene Registry (BGR), a repository pairing clinical genetic data with phenotypic data from participants with variants in putative brain genes. Phenotypic profiles are assembled from the electronic health record (EHR) and a battery of remotely administered standardized assessments collectively referred to as the Rapid Neurobehavioral Assessment Protocol (RNAP), which include cognitive, neurologic, and neuropsychiatric assessments, as well as assessments for attention deficit hyperactivity disorder (ADHD) and autism spectrum disorder (ASD). Co-enrollment of BGR participants in the Clinical Genome Resource's (ClinGen's) GenomeConnect enables display of variant information in ClinVar. The BGR currently contains data on 479 participants who are 55% male, 6% Asian, 6% Black or African American, 76% white, and 12% Hispanic/Latine. Over 200 genes are represented in the BGR, with 12 or more participants harboring variants in each of these genes: CACNA1A, DNMT3A, SLC6A1, SETD5, and MYT1L. More than 30% of variants are de novo and 43% are classified as variants of uncertain significance (VUSs). Mean standard scores on cognitive or developmental screens are below average for the BGR cohort. EHR data reveal developmental delay as the earliest and most common diagnosis in this sample, followed by speech and language disorders, ASD, and ADHD. BGR data has already been used to accelerate gene-disease validity curation of 36 genes evaluated by ClinGen's BGR Intellectual Disability (ID)-Autism (ASD) Gene Curation Expert Panel. In summary, the BGR is a resource for use by stakeholders interested in advancing translational research for brain genes and continues to recruit participants with clinically reported variants to establish a rich and well-characterized national resource to promote research on neurodevelopmental disorders.


Subject(s)
Autism Spectrum Disorder , Autistic Disorder , Intellectual Disability , Neurodevelopmental Disorders , Humans , Male , Female , Autism Spectrum Disorder/genetics , Brain , Registries , Methyltransferases
16.
World J Pediatr Congenit Heart Surg ; 15(4): 525-527, 2024 Jul.
Article in English | MEDLINE | ID: mdl-38646725

ABSTRACT

Persistent junctional reciprocating tachycardia is a rare form of refractory atrioventricular reentrant tachycardia that accounts for <1% of supraventricular tachycardia in pediatrics. The accessory pathways are generally isolated with few reported underlying structural heart defects. We present a case of a five-month-old male with refractory tachyarrhythmia found to have cor triatriatum sinister, which to our knowledge, is the first reported case of these two rare anomalies coexisting.


Subject(s)
Cor Triatriatum , Humans , Cor Triatriatum/complications , Cor Triatriatum/surgery , Male , Infant , Electrocardiography , Tachycardia, Reciprocating/surgery , Tachycardia, Reciprocating/complications , Tachycardia, Reciprocating/physiopathology , Tachycardia, Ectopic Junctional/complications
17.
Chem Biol Drug Des ; 103(4): e14521, 2024 Apr.
Article in English | MEDLINE | ID: mdl-38653576

ABSTRACT

ß-Carboline nucleus is therapeutically valuable in medicinal chemistry for the treatment of varied number of diseases, most importantly cancer. The potent and wide-ranging activity of ß-carboline has established them as imperative pharmacological scaffolds especially in the cancer treatment. Numerous derivatives such as Tetrahydro ß-carbolines, metal complexed ß-carbolines, mono, di and tri substituted ß-carbolines have been reported to possess dynamic anticancer activity. These different substituted ß-carboline derivatives had shown different mechanism of action and plays important role in anticancer drug discovery and development. The review is an update of the chemistry of ß-carbolines, both synthetic and natural origin acting through various targets against cancerous cells. In addition to this, studies of multitarget molecules designed by coupling ß-carbolines along with other mechanisms for treatment of neoplasm are also summarized.


Subject(s)
Antineoplastic Agents , Carbolines , Neoplasms , Carbolines/chemistry , Carbolines/pharmacology , Humans , Antineoplastic Agents/chemistry , Antineoplastic Agents/pharmacology , Neoplasms/drug therapy , Neoplasms/pathology , Animals
18.
Int J Mol Sci ; 25(7)2024 Mar 31.
Article in English | MEDLINE | ID: mdl-38612707

ABSTRACT

Cancers harness embryonic programs to evade aging and promote survival. Normally, sequences at chromosome ends called telomeres shorten with cell division, serving as a countdown clock to limit cell replication. Therefore, a crucial aspect of cancerous transformation is avoiding replicative aging by activation of telomere repair programs. Mouse embryonic stem cells (mESCs) activate a transient expression of the gene Zscan4, which correlates with chromatin de-condensation and telomere extension. Head and neck squamous cell carcinoma (HNSCC) cancers reactivate ZSCAN4, which in turn regulates the phenotype of cancer stem cells (CSCs). Our study reveals a new role for human ZSCAN4 in facilitating functional histone H3 acetylation at telomere chromatin. Next-generation sequencing indicates ZSCAN4 enrichment at telomere chromatin. These changes correlate with ZSCAN4-induced histone H3 acetylation and telomere elongation, while CRISPR/Cas9 knockout of ZSCAN4 leads to reduced H3 acetylation and telomere shortening. Our study elucidates the intricate involvement of ZSCAN4 and its significant contribution to telomere chromatin remodeling. These findings suggest that ZSCAN4 induction serves as a novel link between 'stemness' and telomere maintenance. Targeting ZSCAN4 may offer new therapeutic approaches to effectively limit or enhance the replicative lifespan of stem cells and cancer cells.


Subject(s)
Histones , Telomere , Animals , Mice , Humans , Acetylation , Telomere/genetics , Chromatin/genetics , Aging
19.
bioRxiv ; 2024 Mar 10.
Article in English | MEDLINE | ID: mdl-38496625

ABSTRACT

Despite great progress in the field, chronic Pseudomonas aeruginosa (Pa) infections remain a major cause of morbidity and mortality in patients with cystic fibrosis, necessitating treatment with inhaled antibiotics. Pf phage is a filamentous bacteriophage produced by Pa that has been reported to act as a structural element in Pa biofilms. Pf presence has been associated with resistance to antibiotics and poor outcomes in cystic fibrosis, though the underlying mechanisms are unclear. Here, we have investigated how Pf phages and sputum biopolymers impede antibiotic diffusion using human sputum samples and fluorescent recovery after photobleaching. We demonstrate that tobramycin interacts with Pf phages and sputum polymers through electrostatic interactions. We also developed a set of mathematical models to analyze the complex observations. Our analysis suggests that Pf phages in sputum reduce the diffusion of charged antibiotics due to a greater binding constant associated with organized liquid crystalline structures formed between Pf phages and sputum polymers. This study provides insights into antibiotic tolerance mechanisms in chronic Pa infections and may offer potential strategies for novel therapeutic approaches.

20.
Brain Imaging Behav ; 2024 Mar 23.
Article in English | MEDLINE | ID: mdl-38520594

ABSTRACT

The etiology of brain fog associated with long COVID is not clear. Based on some preliminary work, disruption of the blood-brain barrier has been hypothesized, but has not been tested in patients with long COVID. In this case-control pilot study, we evaluated blood-brain barrier permeability in patients with long COVID and subjective memory loss or brain fog. We used 99 m Technetium diethylenetriaminepentaacetic acid single-photon emission computed tomography (SPECT) to measure blood-brain barrier permeability and a telephone assessment (T-cog) to measure cognitive function. The blood-brain barrier permeability was quantified via SPECT standard uptake value (SUV). We assessed the blood-brain barrier permeability in 14 long COVID patients and 10 control participants without subjective cognitive impairment or brain fog. Participants in the two groups were similar in age. The long COVID group had more comorbidities compared to the control group. There was no difference in the SUVs in the long COVID (0.22 ± 0.12) vs the control (0.17 ± 0.04) group. There was no difference in the T-cog results in the two groups either. We found no evidence of a difference in blood-brain permeability in patients with long COVID when compared to controls without a known history of COVID-19 infection. Larger studies are needed to confirm these findings.

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