FoxO1-GAB1 axis regulates homing capacity and tonic AKT activity in chronic lymphocytic leukemia.

Recirculation of chronic lymphocytic leukemia (CLL) cells between the peripheral blood and lymphoid niches plays a critical role in disease pathophysiology, and inhibiting this process is one of the major mechanisms of action for B-cell receptor (BCR) inhibitors such as ibrutinib and idelalisib. Migration is a complex process guided by chemokine receptors and integrins. However, it remains largely unknown how CLL cells integrate multiple migratory signals while balancing survival in the peripheral blood and the decision to return to immune niches. Our study provided evidence that CXCR4/CD5 intraclonal subpopulations can be used to study the regulation of migration of CLL cells. We performed RNA profiling of CXCR4dimCD5bright vs CXCR4brightCD5dim CLL cells and identified differential expression of dozens of molecules with a putative function in cell migration. GRB2-associated binding protein 1 (GAB1) positively regulated CLL cell homing capacity of CXCR4brightCD5dim cells. Gradual GAB1 accumulation in CLL cells outside immune niches was mediated by FoxO1-induced transcriptional GAB1 activation. Upregulation of GAB1 also played an important role in maintaining basal phosphatidylinositol 3-kinase (PI3K) activity and the "tonic" AKT phosphorylation required to sustain the survival of resting CLL B cells. This finding is important during ibrutinib therapy, because CLL cells induce the FoxO1-GAB1-pAKT axis, which represents an adaptation mechanism to the inability to home to immune niches. We have demonstrated that GAB1 can be targeted therapeutically by novel GAB1 inhibitors, alone or in combination with BTK inhibition. GAB1 inhibitors induce CLL cell apoptosis, impair cell migration, inhibit tonic or BCR-induced AKT phosphorylation, and block compensatory AKT activity during ibrutinib therapy.

miR-29 modulates CD40 signaling in chronic lymphocytic leukemia by targeting TRAF4: an axis affected by BCR inhibitors.

B-cell receptor (BCR) signaling and T-cell interactions play a pivotal role in chronic lymphocytic leukemia (CLL) pathogenesis and disease aggressiveness. CLL cells can use microRNAs (miRNAs) and their targets to modulate microenvironmental interactions in the lymph node niches. To identify miRNA expression changes in the CLL microenvironment, we performed complex profiling of short noncoding RNAs in this context by comparing CXCR4/CD5 intraclonal cell subpopulations (CXCR4dimCD5bright vs CXCR4brightCD5dim cells). This identified dozens of differentially expressed miRNAs, including several that have previously been shown to modulate BCR signaling (miR-155, miR-150, and miR-22) but also other candidates for a role in microenvironmental interactions. Notably, all 3 miR-29 family members (miR-29a, miR-29b, miR-29c) were consistently down-modulated in the immune niches, and lower miR-29(a/b/c) levels associated with an increased relative responsiveness of CLL cells to BCR ligation and significantly shorter overall survival of CLL patients. We identified tumor necrosis factor receptor-associated factor 4 (TRAF4) as a novel direct target of miR-29s and revealed that higher TRAF4 levels increase CLL responsiveness to CD40 activation and downstream nuclear factor-κB (NF-κB) signaling. In CLL, BCR represses miR-29 expression via MYC, allowing for concurrent TRAF4 upregulation and stronger CD40-NF-κB signaling. This regulatory loop is disrupted by BCR inhibitors (bruton tyrosine kinase [BTK] inhibitor ibrutinib or phosphatidylinositol 3-kinase [PI3K] inhibitor idelalisib). In summary, we showed for the first time that a miRNA-dependent mechanism acts to activate CD40 signaling/T-cell interactions in a CLL microenvironment and described a novel miR-29-TRAF4-CD40 signaling axis modulated by BCR activity.

A De Novo HECW2 Variant in a Patient with Acetazolamide-Responsive Episodic Ataxia.

To the best of our knowledge, this is the first case to address episodic ataxia (EA) as a possible phenotypic feature of HECW2-related disorder. This single case study describes a 26-year-old female born at term with mild intellectual disability, neonatal hypotonia, and a history of febrile seizures who presented with paroxysmal events since the age of 2. These episodes include frequent falls due to imbalance, dilated pupils, vertigo, diaphoresis, nausea, vomiting, and nystagmus. Brain imaging was normal. A prolonged electroencephalogram (EEG) revealed interictal epileptiform discharges but failed to capture her clinical events. For several years, she was treated for presumed focal seizures with preserved awareness and trialed on adequate dosing of several antiepileptic medications without improvement. After 25 years, given the more prolonged nature of her episodes and the mild interictal cerebellar signs, empiric treatment with acetazolamide was initiated for a presumed diagnosis of EA. Acetazolamide treatment led to a dramatic reduction in event frequency and severity. The initial EA genetic panel was negative. Clinical exome sequence analysis revealed a novel pathogenic de novo missense variant in the HECW2 gene [c.3829 T > C;(p.Tyr1277His)], located in the HECT domain. HECW2 variants are associated with neurodevelopmental delay, hypotonia, and epilepsy. This study expands the genetic and clinical spectrum of HECW2-related disorder and adds EA to the phenotypic spectrum in affected individuals.

Promoting Equity, Diversity, and Inclusion in Medicine: A Comprehensive Toolkit for Change in Radiology.

This toolkit presents a comprehensive framework for a toolkit intended to increase equity, diversity, and inclusion (EDI) within the medical field and recommendations. We advocate for clear, comprehensive definitions and interpretations of fundamental EDI terms, laying the groundwork necessary for initiating and maintaining EDI initiatives. Furthermore, we offer a systematic approach to establishing EDI committees within medical departments, accentuating the pivotal role these committees play as they drive and steer EDI strategies. This toolkit also explores strategies tailored for the recruitment of a diverse workforce. This includes integral aspects such as developing inclusive job advertisements, implementing balanced search methods for candidates, conducting unbiased appraisals of applications, and structuring diverse hiring committees. The emphasis on these strategies not only augments the diversity within medical institutions but also sets the stage for a more holistic approach to healthcare delivery. Therefore, by adopting the recommended strategies and guidelines outlined in this framework, medical institutions and specifically radiology departments can foster an environment that embodies inclusivity and equity, thereby enhancing the quality of patient care and overall health outcomes.

Recommendations for Improvement of Equity, Diversity, and Inclusion in the CaRMs Selection Process.

Equity, diversity and inclusion (EDI) in the medical field is crucial for meeting the healthcare needs of a progressively diverse society. A diverse physician workforce enables culturally sensitive care, promotes health equity, and enhances the comprehension of the various needs and viewpoints of patients, ultimately resulting in more effective treatments and improved patient outcomes. However, despite the recognized benefits of diversity in the medical field, certain specialties, such as Radiology, have struggled to achieve adequate equity, diversity and inclusion, which results in a discrepancy in the demographics of Canadian radiologists and the patients we serve. In this review, we propose strategies from a committee within the Canadian Association of Radiologists (CAR) EDI working group to improve EDI in the CaRMS selection process. By adopting these strategies, residency programs can foster a more diverse and inclusive environment that is better positioned to address the health needs of a progressively diverse patient population, leading to improved patient outcomes, greater patient satisfaction, and advancements in medical innovation.

Correlation of Body Mass Index with Anthropometric and Biochemical Parameters Among Polycystic Ovary Syndrome Phenotypes.

This was a prospective observational study, conducted at a tertiary care health centre in Rajasthan. A total of 68 women with PCOS (Rotterdam criteria) attending OPD at Department of Obstetrics and Gynecology qualified as per inclusion and exclusion criteria were included in the study. Each participant was examined for anthropometric and biochemical parameters. The largest phenotypic group was phenotype A, (41.17%); followed by B (26.47%); C (20.58%), and D (P + O) phenotypes (11.76%). Hyperandrogenic phenotypes (A, B, C), had significantly higher prevalence of deranged serum glucose (fasting and postprandial), lipid profile and serum TSH than normoandrogenic phenotype D. BMI was strongly correlated with anthropometric (p < 0.001) and biochemical parameters (p < 0.05) in phenotype A among four phenotypes of PCOS. Phenotype A was the most common form of PCOS and a strong correlation of BMI with waist circumference (WC), dyslipidemia and Sub-clinical hypothyroidism (SCH) was observed in women of this phenotype of PCOS. These results indicate that phenotype A is at increased risk of CVD and diabetes and phenotype D has least metabolic risks.

Rescue therapies in epilepsy.

PURPOSE OF REVIEW: The purpose of this review is to provide a succinct evaluation of the current rescue medications and action plans available to our patients with seizure clusters in the outpatient setting. RECENT FINDINGS: The main themes of the recent findings are that rescue medications and seizure action plans (SAPs) are underutilized, particularly in the adult population. The safety and efficacy of intranasal midazolam and intranasal diazepam is comparable with rectal diazepam for the treatment of seizure clusters. Additionally, this intranasal formulation has the benefit of a more socially acceptable route of administration and ease of use. SUMMARY: The implication of these findings is a greater variety and awareness in the rescue medications available to our patients suffering from seizure clusters.

Second-Degree Burns and Aloe Vera: A Meta-analysis and Systematic Review.

OBJECTIVE: Aloe vera is a cost-effective, accessible wound care adjunct with a minimal risk profile. Despite its centuries-long history being used to treat varying wound types, published reports remain inconclusive on its efficacy. In this article, the authors report the results of a systematic review assessing the efficacy of topical aloe vera products in wound care applications, as well as a meta-analysis of its utility in burn healing where data are most robust. DATA SOURCES: In accordance with PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) guidelines, the authors searched PubMed, EMBASE, and Cochrane CENTRAL for randomized controlled trials assessing the use of aloe vera in healing various wound types. STUDY SELECTION: The database search identified 91 articles. After duplicates were removed, 74 articles were screened, and of those, 47 were assessed for eligibility. Ultimately, 28 articles were included in the qualitative synthesis, and 4 studies assessing second-degree burns were included in the meta-analysis. DATA EXTRACTION: The following data points were collected from each study: number of participants/wounds, treatment type, adjunctive therapy (if any), and primary outcomes. DATA SYNTHESIS: Risk-of-bias analysis was conducted on included articles, and results were compiled. A meta-analysis was undertaken for studies focusing on the treatment of burns. Cumulatively, these studies had a total of 133 patients with 163 wounds being assessed. Analysis revealed a statistically significant mean difference in time to healing of 4.44 days in favor of aloe vera treatment (P = .004). CONCLUSIONS: Topical aloe vera usage for second-degree burn wound healing demonstrated significantly faster time to healing compared with other treatments.

Amniotic fluid-derived multipotent stromal cells drive diabetic wound healing through modulation of macrophages.

BACKGROUND: Cutaneous wounds in patients with diabetes exhibit impaired healing due to physiological impediments and conventional care options are severely limited. Multipotent stromal cells (MSCs) have been touted as a powerful new therapy for diabetic tissue repair owing to their trophic activity and low immunogenicity. However, variations in sources and access are limiting factors for broader adaptation and study of MSC-based therapies. Amniotic fluid presents a relatively unexplored source of MSCs and one with wide availability. Here, we investigate the potential of amniotic fluid-derived multipotent stromal cells (AFMSCs) to restore molecular integrity to diabetic wounds, amend pathology and promote wound healing. METHOD: We obtained third trimester amniotic fluid from term cesarean delivery and isolated and expanded MSCs in vitro. We then generated 10 mm wounds in Leprdb/db diabetic mouse skin, and splinted them open to allow for humanized wound modeling. Immediately after wounding, we applied AFMSCs topically to the sites of injuries on diabetic mice, while media application only, defined as vehicle, served as controls. Post-treatment, we compared healing time and molecular and cellular events of AFMSC-treated, vehicle-treated, untreated diabetic, and non-diabetic wounds. A priori statistical analyses measures determined significance of the data. RESULT: Average time to wound closure was approximately 19 days in AFMSC-treated diabetic wounds. This was significantly lower than the vehicle-treated diabetic wounds, which required on average 27.5 days to heal (p < 0.01), and most similar to time of closure in wild type untreated wounds (an average of around 18 days). In addition, AFMSC treatment induced changes in the profiles of macrophage polarizing cytokines, resulting in a change in macrophage composition in the diabetic wound bed. We found no evidence of AFMSC engraftment or biotherapy induced immune response. CONCLUSION: Treatment of diabetic wounds using amniotic fluid-derived MSCs encourages cutaneous tissue repair through affecting inflammatory cell behavior in the wound site. Since vehicle-treated diabetic wounds did not demonstrate accelerated healing, we determined that AFMSCs were therapeutic through their paracrine activities. Future studies should be aimed towards validating our observations through further examination of the paracrine potential of AFMSCs. In addition, investigations concerning safety and efficacy of this therapy in clinical trials should be pursued.

Impact of COVID-19 pandemic on cancer surgery: Patient's perspective.

BACKGROUND: Coronavirus disease 2019 (COVID-19) has impacted cancer care globally. The aim of this study is to analyze the impact of COVID-19 on cancer healthcare from the perspective of patients with cancer. METHODS: A cross-sectional survey was conducted between June 19, 2020, to August 7, 2020, using a questionnaire designed by patients awaiting cancer surgery. We examined the impact of COVID-19 on five domains (financial status, healthcare access, stress, anxiety, and depression) and their relationship with various patient-related variables. Factors likely to determine the influence of COVID-19 on patient care were analyzed. RESULTS: A significant adverse impact was noted in all five domains (p = < 0.05), with the maximal impact felt in the domain of financial status followed by healthcare access. Patients with income levels of INR < 35 K (adjusted odds ratio [AOR] = 1.61, p < 0.05), and 35K- 100 K (AOR = 1.96, p < 0.05), married patients (AOR = 3.30, p < 0.05), and rural patients (AOR = 2.82, p < 0.05) experienced the most adverse COVID-19-related impact. CONCLUSION: Delivering quality cancer care in low to middle-income countries is a challenge even in normal times. During this pandemic, deficiencies in this fragile healthcare delivery system were exacerbated. Identification of vulnerable groups of patients and strategic utilization of available resources becomes even more important during global catastrophes, such as the current COVID-19 pandemic. Further work is required in these avenues to not only address the current pandemic but also any potential future crises.

miR-150 downregulation contributes to the high-grade transformation of follicular lymphoma by upregulating FOXP1 levels.

Follicular lymphoma (FL) is a common indolent B-cell malignancy with a variable clinical course. An unfavorable event in its course is histological transformation to a high-grade lymphoma, typically diffuse large B-cell lymphoma. Recent studies show that genetic aberrations of MYC or its overexpression are associated with FL transformation (tFL). However, the precise molecular mechanisms underlying tFL are unclear. Here we performed the first profiling of expression of microRNAs (miRNAs) in paired samples of FL and tFL and identified 5 miRNAs as being differentially expressed. We focused on one of these miRNAs, namely miR-150, which was uniformly downmodulated in all examined tFLs (∼3.5-fold), and observed that high levels of MYC are responsible for repressing miR-150 in tFL by binding in its upstream region. This MYC-mediated repression of miR-150 in B cells is not dependent on LIN28A/B proteins, which influence the maturation of miR-150 precursor (pri-miR-150) in myeloid cells. We also demonstrated that low miR-150 levels in tFL lead to upregulation of its target, namely FOXP1 protein, which is a known positive regulator of cell survival, as well as B-cell receptor and NF-κB signaling in malignant B cells. We revealed that low levels of miR-150 and high levels of its target, FOXP1, are associated with shorter overall survival in FL and suggest that miR-150 could serve as a good biomarker measurable in formalin-fixed paraffin-embedded tissue. Overall, our study demonstrates the role of the MYC/miR-150/FOXP1 axis in malignant B cells as a determinant of FL aggressiveness and its high-grade transformation.

Are Bioceramics the Dernier Cri in the Management of Stage 4 Developed Root? A Finite Element Analysis.

AIM: To compare the stress distribution of four modalities of reinforcing the radicular space of a pulpless central incisor exhibiting stage 4 root development. MATERIALS AND METHODS: The model of a pulpless immature central incisor with a stage 4 of root development supporting periodontium was generated based on the properties. The longitudinal growth of the root was completed. Four such models were developed. Then, the radicular space was rehabilitated as follows: Model 1: Ceramicrete; Model 2: Biomimetic Mineralization; Model 3: Biodentine; Model 4: Bioaggregate. They were subjected to three different loading conditions. One was to mimic the mastication by applying a load of 70 N applied at 45° angle. Second loading condition was a vertical load of 100 N to mimic bruxism. The third loading condition was to mirror the impact of a frontal trauma. A load of 100 N was applied labially. RESULTS: It was observed that during mastication, Model 2 has exhibited the lowest concentration of von Mises stresses, followed by Model 3 and then Model 4 followed by Model 1; this could be because the modulus of elasticity of Model 2 is comparable to that of Dentin. During bruxism and horizontal impact, the maximal stress concentration was found in Model 4, Model 3, Model 2, followed by Model 1. CONCLUSION: The closer the elasticity of modulus of the primary endodontic replacement monoblock was to that of dentin, the lower were the stresses generated. However, as the increase in stress values was minimal between groups, these obturating materials can be viable reinforcement materials for the rehabilitation of cases of stage 4 developing root. Biomimetic mineralization strategies can be a viable treatment option for managing cases of the open apex. CLINICAL RELEVANCE: Biomimetic mineralization strategies and bioceramics can be used for obturation of root canals with open apex, instead of utilizing these bioceramics as apical plugs.

Obesity genetics and cardiometabolic health: Potential for risk prediction.

The increasing burden of obesity worldwide and its effect on cardiovascular disease (CVD) risk is an opportunity for evaluation of preventive approaches. Both obesity and CVD have a genetic background and polymorphisms within genes which enhance expression of variant proteins that influence CVD in obesity. Genome-based prediction may therefore be a feasible strategy, but the identification of genetically driven risk factors for CVD manifesting as clinically recognized phenotypes is a major challenge. Clusters of such risk factors include hyperglycaemia, hypertension, ectopic liver fat, and inflammation. All involve multiple genetic pathways having complex interactions with variable environmental influences. The factors that make significant contributions to CVD risk include altered carbohydrate homeostasis, ectopic deposition of fat in muscle and liver, and inflammation, with contributions from the gut microbiome. A futuristic model depends on harnessing the predictive power of plausible genetic variants, phenotype reversibility, and effective therapeutic choices based on genotype-phenotype interactions. Inverting disease phenotypes into ideal cardiovascular health metrics could improve genetic and epigenetic assessment, and form the basis of a future model for risk detection and early intervention.

Risk Factors for Wound Complications Following Transmetatarsal Amputation in Patients With Diabetes.

BACKGROUND: The goal of our study was to evaluate risk factors for wound complications in patients with diabetes mellitus undergoing transmetatarsal amputations (TMAs), given the paucity of research on this subject. MATERIALS AND METHODS: We used the American College of Surgeons National Surgical Quality Improvement Program database. In this retrospective analysis, all surgical cases with a primary Current Procedural Terminology code for TMA from 2009 to 2015 were reviewed. RESULTS: A total of 2316 patients with diabetes mellitus who underwent TMA were identified. Overall wound complications occurred in 276 (11.9%) of patients. Univariate analysis showed that the operative time was significantly longer in patients who developed complications than those who did not (58.3 ± 39.5 versus 50.6 ± 39.4; P = 0.003). Furthermore, the rate of obesity was significantly higher among patients who developed wound complications than those who did not (47.1% versus 41.5%; P = 0.04). Multivariate analysis demonstrated that a longer operative time (odds ratio = 1.02; 95% confidence interval: 1.01-1.04; P = 0.01) and obesity (odds ratio = 1.60; 95% confidence interval: 1.06-2.40; P = 0.03) were independent risk factors for wound complications in our cohort. CONCLUSIONS: These findings emphasize the importance of having heightened clinical vigilance in obese patients with diabetes mellitus undergoing this procedure, close postoperative follow-up, and limiting operative time when possible.

A novel Nanoformulation Development of Eugenol and their treatment in inflammation and periodontitis.

OBJECTIVE: To prepare a novel nanoemulsion- Carbopol® 934 gel for Eugenol, in order to prevent the periodontitis. MATERIAL AND METHODS: Spontaneous emulsification method was used for the preparation of nanoemulsion in which it contain Eugenol (oil phase), Tween-80 (surfactant), and PEG (co-surfactant). To the development of best nanoemulsion, three-factor three-level central composite design was used in which %oil; %Smix and % water were optimized as independent variables. An optimized-nanoemulsion were converted to nanoemulsion-Carbopol® 934 gel. RESULTS: 5.5% oil, 35.5% Smix and 59.0% water were optimized as independent and dependent variables. Finally dependent variables optimized as a particle size (nm), PDI and %transmittance were observed 79.92 ±â€¯6.33 nm, 0.229 ±â€¯0.019, and 98.88 ±â€¯1.31% respectively. The values of final results for dependent variables like particle size (nm), PDI and % transmittance were evaluated as 79.92 ±â€¯6.33 nm, 0.229 ±â€¯0.019, and 98.88 ±â€¯1.31%, respectively. TEM and SEM showed a spherical shape of developed nanoemulsion with refractive index (1.63 ±â€¯0.038), zeta potential (-19.16 ±â€¯0.11), pH (7.4 ±â€¯0.06), viscosity (34.28 ±â€¯6 cp), and drug content of 98.8 ±â€¯0.09%. After that a final optimized EUG-NE-Gel was assessed on the basis of their pH measurement, drug content, syringeability, and mucoadhesion on the goat buccal mucosa. Optimized EUG-NE-Gel (Tween-80 and Carbopol® 934 used) showed the results, to improve the periodontal drug delivery of EUG in future. CONCLUSION: EUG-NE-Gel showed a significant role in anti-inflammatory activity, analgesic, and anesthetic, antibacterial, and treatment of periodontal disease.