Stretching the structural envelope of imatinib to reduce ß-amyloid production by modulating both ß- and γ-secretase cleavages of APP.

We previously showed that the anticancer drug imatinib mesylate (IMT, trade name: Gleevec) and a chemically distinct compound, DV2-103 (a kinase-inactive derivative of the potent Abl and Src kinase inhibitor, PD173955) lower Aß levels at low micromolar concentrations primarily through a lysosome-dependent mechanism that renders APP less susceptible to proteolysis by BACE1 without directly inhibiting BACE1 enzymatic activity, or broadly inhibiting the processing of other BACE1 substrates. Additionally, IMT indirectly inhibits γ-secretase and stimulates autophagy, and thus may decrease Aß levels through multiple pathways. In two recent studies we demonstrated similar effects on APP metabolism caused by derivatives of IMT and DV2-103. In the present study, we synthesized and tested radically altered IMT isomers (IMTi's) that possess medium structural similarity to IMT. Independent of structural similarity, these isomers manifest widely differing potencies in altering APP metabolism. These will enable us to choose the most potent isomers for further derivatization.

The Relationship of Carotid and Brachial Artery Wall Thickness Measurement with Cardiovascular Risk Scoring in Individuals Living with HIV.

Objective: This study aimed to investigate whether human immunodeficiency virus (HIV) infection affects carotid and brachial artery wall thickness and whether measurement of this thickness contributes to traditional cardiovascular risk scoring in individuals living with HIV. Materials and Methods: The patient group included people living with HIV who were followed up in the infectious disease clinic, and the control group included patients without HIV. In both groups, carotid artery intima-media thickness (cIMT) was measured with B-mode ultrasonography (B-USG). cIMT 0.9 mm and above was considered subclinical atherosclerosis. Results: The patient group consisted of 66, and the control group consisted of 40 participants. The median cIMT of the patient and control groups was 0.92 (0.45-1.45) mm and 0.55 (0.35-1.25) mm, respectively (p<0.001). Brachial artery IMT was significantly higher in the patient group with 0.45 (0.30-0.76) mm, while it was 0.35 (0.17-0.50) mm in the control group (p<0.001). Although the difference between the cIMT and brachial artery IMT results of the patient and control groups was significant between 18-59 years of age, this difference disappeared in older ages. In the patient group, subclinical atherosclerosis was detected with cIMT in individuals under 30 years of age for whom FRS (Framingham risk score) could not be calculated and in low-risk groups according to FRS (20% and 62.9%, respectively). Conclusion: cIMT and brachial artery IMT were found to be significantly higher in people living with HIV. The cIMT measurement seems to be very useful in calculating the CVD risk in individuals living with HIV, especially at young ages, in catching patients who are overlooked by traditional scoring systems.

A rare case of inflammatory myofibroblastic tumour of the thigh : A case report and literature review.

Towards the beginning of the twentieth century, inflammatory myofibroblastic tumors were described as neoplasms characterized by myofibroblastic spindle cells with an infiltrate of inflammatory cells. These rare tumors occur mainly in children and young adults with a preferential pulmonary and abdominal location. They have intermediate biological potency with a tendency to local recurrence and rarely metastasize. We describe the case of an adolescent who presented with an inflammatory myofibroblastic tumor of the thigh, a very rare entity that has only been reported in the literature as case reports, and its clinical, radiological, echographic and MRI appearance. The patient underwent complete surgical resection of the mass with healthy margins and did not receive any additional treatment. No sign of recurrence was detected after 6 months of follow-up.

Left versus right carotid artery IMT: differential impact of age, gender, and cardiovascular risk factors.

Carotid artery intima-media thickness (IMT), an important clinical marker of atherosclerosis, is used widely in screening for cardiovascular risk and prognosis. Measurements of carotid artery IMT are made on both the left and right sides of the body, however as per the Mannheim consensus, an average of these measurements is usually reported. Nevertheless, there is considerable debate whether there are side differences in the carotid artery IMT in terms of both measurements and determinants. In a large sample of Caucasian patients (n = 1888) referred for cardiovascular risk assessment, we compared the left and the right common carotid artery IMT measurements, and assessed whether age, gender and cardiovascular risk factors have differential effects. We found that the left common carotid artery IMT (0.7141 ± 0.1733 mm) is larger than the right (0.6861 ± 0.1594, p < 0.0001), but not in the young (< 30 years) or the elderly (> 69 years), and that this side difference is less in women (0.019 ± 0.116 mm) than in men (0.036 ± 0.148 mm, p < 0.001). In addition to age (p < 0.0001) and gender (p < 0.0001), the left common carotid artery IMT was determined by dyslipidaemia (protective, p = 0.016) and diabetes mellitus (p = 0.022); whereas the right common carotid artery IMT was determined by hypertension (p = 0.0002). The differential determinants of left versus right common carotid artery IMT were similar in men and women, and in young and old. In conclusion, side differences in measurements of the common carotid artery IMT depend upon age and gender. In addition, cardiovascular risk factors have differential effects on the left and right common carotid artery IMT.

Circulating Angiopoietin-like Protein 6 Levels and Clinical Features in Patients with Type 2 Diabetes.

Aims The main purpose of this study was to evaluate the associations between circulating angiopoietin-like protein 6 (ANGPTL6) levels and various diabetes- and atherosclerosis-related variables in patients with type 2 diabetes. Methods Serum ANGPTL6 levels in patients with type 2 diabetes hospitalized for glycemic control and/or diabetic education were measured using a chemiluminescent immunoassay (CLIA). Results Most patients had elevated HbA1c levels; 85.7% and 71.4% of patients had HbA1c levels of (8% and (9%, respectively. ANGPTL6 levels were significantly higher in patients with type 2 diabetes than in non-diabetic controls. In patients with type 2 diabetes, ANGPTL6 was significantly and positively correlated with the duration of diabetes, systolic blood pressure (SBP), gamma-glutamyl transpeptidase (GGT), C-reactive protein (CRP), and the intimal medial complex thickness of the carotid artery (IMT), and inversely correlated with hemoglobin A1c (HbA1c). In the multiple regression analysis, ANGPTL6 had a significant positive association with triglyceride (TG) in one of the models in which it was included as a variable. Furthermore, ANGPTL6 also showed significant positive associations with CRP and IMT in models in which they were included as variables. Conclusion The current study suggests that circulating levels of ANGPTL6 may be negatively associated with poor glycemic control and positively associated with the degree of atherosclerosis, as reflected by IMT, in patients with type 2 diabetes, most of whom had elevated HbA1c levels.

Inflammatory Myofibroblastic Tumor of the Lung: A Report of a Rare Case.

The uncommon and mysterious pulmonary inflammatory myofibroblastic tumor (PIMT) primarily affects children and young people. PIMT is characterized by the proliferation of myofibroblastic spindle cells mixed with inflammatory cells. It can resemble both benign and malignant disorders, both radiographically and clinically. PIMT typically manifests as a solitary lung tumor. The genesis of the tumor is linked to genetic anomalies, including those related to the ALK gene (anaplastic lymphoma kinase); nonetheless, some cases are not ALK-positive, indicating genetic variability. Clinically, patients may have non-specific symptoms such as cough, chest pain, or hemoptysis, or they may not exhibit any symptoms at all. In these cases, imaging tests may unintentionally reveal unrelated conditions. From a histopathological perspective, PIMT is characterized by a heterogeneous cellular makeup, encompassing lymphocytes, myofibroblasts, plasma cells, and histiocytes, which generally exhibit a fascicular or storiform pattern. The diagnosis is verified using immunohistochemical labeling, molecular research, and histological examination. The cornerstone of treatment is still surgical resection, which has a good prognosis and a low recurrence rate. On the other hand, specific treatments, such as ALK inhibitors, have shown promise for incurable or recurring instances. Even though PIMT usually has a benign history, it is important to comprehend its biological behavior and molecular foundations for precise diagnosis and efficient management. This underscores the need for additional study into the pathophysiology and potential treatments of PIMT. This report presents a case of a 53-year-old female who presented with complaints of breathlessness and chest pain and was diagnosed with the condition accidentally.

Recurrent Inflammatory Myofibroblastic Tumor of Larynx Harboring a Novel THBS1::ALK Fusion.

Inflammatory myofibroblastic tumor (IMT) is a rare soft tissue tumor primarily occurring in the abdominopelvic region of young patients, and it is characterized by spindle-shaped myofibroblasts, or fibroblasts surrounded by inflammatory infiltrate. Herein, we report a case of a 24-year-old male with a firm submucosal mass in the anterior right vocal fold diagnosed as an IMT that recurred 14 months later. The tumor demonstrated a novel THBS1::ALK fusion containing Exons 1-7 of the thrombospondin 1 (THBS1) gene fused to Exon 19 of the anaplastic lymphoma kinase (ALK) gene via next-generation sequencing with the NextSeq sequencer. The fusion of THBS1 to ALK potentially results in increased expression and constitutive activation of the ALK kinase domain. These findings not only broaden the repertoire of known ALK fusion partners implicated in tumorigenesis but also provide a novel avenue for investigating the etiology of recurrent IMT by considering this fusion event as a causal factor. To our knowledge, this is the second case of IMT of the larynx with this novel mutation reported in the literature and the first such case with a detailed description of this specific fusion and clinical recurrence.

SING IMT in pseudophakic eyes: Results of the first experiences.

Purpose: To evaluate the feasibility and outcomes of implanting the Smaller-Incision New-Generation Implantable Miniature Telescope (SING IMT) in pseudophakic patients affected by late-stage dry AMD. Subjects: Five pseudophakic patients' eyes with stable dry AMD were suitable for SING IMT implantation. Four eyes were excluded because of previous YAG laser capsulotomy. Patients underwent preoperative assessments, including visual acuity measurements and OCT scans. Methods: Surgical procedures were performed under peribulbar anesthesia, with careful IOL removal and SING IMT implantation. Postoperative follow-up was conducted at regular intervals to monitor visual acuity, device positioning and complications. Results: Postoperative outcomes demonstrated improvements in visual acuity for most patients with an average gain in CDVA (Corrected Distance Visual Acuity) and CNVA (Corrected Near Visual Acuity) of 16,8 ± 10,2 and 13,8 ± 7,4 ETDRS letters, respectively. Limited complications have been observed. In one case, we observed dislocation of the device into the vitreous chamber, which we managed through vitrectomy and scleral fixation of the SING IMT using GoreTex suture. Conclusions: Despite being traditionally contraindicated for pseudophakic patients, SING IMT implantation in selected cases yielded favorable outcomes, indicating potential benefits for this population. Further research with larger sample sizes and longer follow-up periods is warranted to refine patient selection criteria and optimize surgical techniques.

Inflammatory myofibroblastic tumor from molecular diagnostics to current treatment.

Inflammatory myofibroblastic tumor (IMT) is a rare neoplasm with intermediate malignancy characterized by a propensity for recurrence but a low metastatic rate. Diagnostic challenges arise from the diverse pathological presentation, variable symptomatology, and lack of different imaging features. However, IMT is identified by the fusion of the anaplastic lymphoma kinase (ALK) gene, which is present in approximately 70% of cases, with various fusion partners, including ran-binding protein 2 (RANBP2), which allows confirmation of the diagnosis. While surgery is the preferred approach for localized tumors, the optimal long-term treatment for advanced or metastatic disease is difficult to define. Targeted therapies are crucial for achieving sustained response to treatment within the context of genetic alteration in IMT. Crizotinib, an ALK tyrosine kinase inhibitor (TKI), was officially approved by the US Food and Drug Administration (FDA) in 2020 to treat IMT with ALK rearrangement. However, most patients face resistance and disease progression, requiring consideration of sequential treatments. Combining radiotherapy with targeted therapy appears to be beneficial in this indication. Early promising results have also been achieved with immunotherapy, indicating potential for combined therapy approaches. However, defined recommendations are still lacking. This review analyzes the available research on IMT, including genetic disorders and their impact on the course of the disease, data on the latest targeted therapy regimens and the possibility of developing immunotherapy in this indication, as well as summarizing general knowledge about prognostic and predictive factors, also in terms of resistance to systemic therapy.

Inflammatory myofibroblastic tumor of the adrenal gland: A case report.

Inflammatory Myofibroblastic Tumor (IMT) occurring in the adrenal gland is extremely rare, and pathologic examination is the gold standard for confirming the diagnosis. We report a case of IMT of adrenal origin in a patient whose diagnosis was confirmed by pathological examination after surgical resection of the tumor. Although previous studies have reported an overall favorable prognosis for IMT, regular and long-term follow-up is necessary.

Pediatric skull inflammatory myofibroblastic tumor: a rare case report and literature review.

Inflammatory myofibroblastic tumors (IMTs) represent rare neoplasms, particularly infrequent in the pediatric skull. We present a novel case of a newborn male with a 5 cm right temporal mass and discuss current diagnostic and treatment options for IMTs. A multidisciplinary effort to surgically remove the lesion was successful, and the patient's skull defect healed without neurological deficits. The etiology of IMTs remains elusive, with proposed associations with chromosomal mutations in the anaplastic lymphoma kinase (ALK) gene. Surgical excision remains the primary treatment for IMTs. Promising pharmacological treatments, like Crizotinib, warrant further research into understanding potential alternatives in IMT management.

Population modeling analyses of crizotinib in pediatric patients with ALK-positive advanced cancers.

BACKGROUND: Alterations in the ALK (anaplastic lymphoma kinase) gene play a critical role in pathogenesis of anaplastic large cell lymphoma (ALCL). Crizotinib is a small molecule competitive inhibitor of ALK, ROS1, and MET kinases and was approved for pediatric patients with ALK-positive relapsed or refractory, systemic ALCL, and ALK-positive unresectable, recurrent, or refractory inflammatory myofibroblastic tumors (IMT). PROCEDURE: Crizotinib data from pediatric patients with relapsed or refractory solid tumors, IMT, or ALCL were included in the analyses. All patients received crizotinib orally at doses ranging from 100 to 365 mg/m2 twice daily (BID). PopPK analyses were conducted to characterize crizotinib disposition in pediatric patients. Exposure-response (ER) safety and antitumor analyses were conducted to characterize relationships between crizotinib dose or exposure with safety and antitumor activity endpoints of interest. RESULTS: The population pharmacokinetic (popPK), ER safety, and ER antitumor analysis included 98, 110, and 36 pediatric patients, respectively. A one-compartment pharmacokinetic model with allometric scaling, first-order elimination, and first-order absorption with lag time adequately described the data. Natural log-transformed model-predicted crizotinib AUCss (steady-state area under the concentration-time curve) demonstrated a significant, positive relationship with Grade ≥3 NEUTROPENIA and Any Grade VISION DISORDER. Crizotinib dose demonstrated a positive relationship with objective response rate. CONCLUSIONS: No significant differences in PK were identified across a wide range of ages or across tumor types, suggesting body surface area (BSA)-based dosing adequately adjusted for differences in patient size to achieve similar systemic crizotinib exposures across young children and adolescent pediatric patients. None of the myelosuppressive events except Grade ≥3 NEUTROPENIA had significant relationships identified with crizotinib dose or exposure, suggesting crizotinib is a tolerable treatment with less hematological toxicity than traditional chemotherapy regimens for pediatric patients with ALK-mutated cancers. Results from the presented analyses support the pediatric dosing recommendations in the product label.

Inflammatory Myofibroblastic Tumor After Receiving Treatment for Non-small Cell Carcinoma.

Inflammatory pseudotumor encompasses a spectrum of both neoplastic and non-neoplastic conditions characterized by a histological pattern featuring a proliferation of cytologically bland spindle cells, accompanied by a prominent chronic inflammatory infiltrate. Within this spectrum, inflammatory myofibroblastic tumor (IMT) has emerged as a distinct entity over the past two decades, marked by unique clinical, pathological, and molecular characteristics. Typically affecting the visceral soft tissues of children and adolescents, IMT exhibits a propensity for local recurrence while posing a minimal risk of distant metastasis. They are extremely rare in adults, constituting less than 1% of adult lung tumors. Our patient, a 63-year-old female, has an intricate medical background, encompassing chronic obstructive pulmonary disease (COPD), a previous history of smoking (35 pack-years, quit a year before admission), coronary artery disease, non-obstructive hypertrophic cardiomyopathy, and obstructive sleep apnea. Presenting with a diagnostic dilemma, she recently received treatment for non-small cell carcinoma with radiation therapy, which has evolved into a swiftly advancing case of IMT.

Advances in uterine inflammatory myofibroblastic tumours: Diagnostic challenges and risk stratification.

The current understanding of inflammatory myofibroblastic tumours (IMTs) of the gynaecological tract has recently been enhanced by their increased recognition. This increase is largely due to greater accessibility to RNA-based molecular assays used to identify their defining ALK rearrangements. This review summarises the clinical characteristics, morphological spectrum, immunohistochemical profile and molecular underpinnings of uterine IMT. Additionally, this review discusses practical diagnostic considerations including overlap between uterine IMT and smooth muscle tumours as well as pregnancy-associated uterine IMT. Finally, we highlight recent literature demonstrating the potential for aggressive behaviour in uterine IMT, including a novel risk stratification model for identifying high-risk IMT.

CFAP58 is involved in the sperm head shaping and flagellogenesis of cattle and mice.

CFAP58 is a testis-enriched gene that plays an important role in the sperm flagellogenesis of humans and mice. However, the effect of CFAP58 on bull semen quality and the underlying molecular mechanisms involved in spermatogenesis remain unknown. Here, we identified two single-nucleotide polymorphisms (rs110610797, A>G and rs133760846, G>T) and one indel (g.-1811_ g.-1810 ins147bp) in the promoter of CFAP58 that were significantly associated with semen quality of bulls, including sperm deformity rate and ejaculate volume. Moreover, by generating gene knockout mice, we found for the first time that the loss of Cfap58 not only causes severe defects in the sperm tail, but also affects the manchette structure, resulting in abnormal sperm head shaping. Cfap58 deficiency causes an increase in spermatozoa apoptosis. Further experiments confirmed that CFAP58 interacts with IFT88 and CCDC42. Moreover, it may be a transported cargo protein that plays a role in stabilizing other cargo proteins, such as CCDC42, in the intra-manchette transport/intra-flagellar transport pathway. Collectively, our findings reveal that CFAP58 is required for spermatogenesis and provide genetic markers for evaluating semen quality in cattle.

Reclassification of a spindle cell sarcoma after identification of a TFG-ROS1 fusion: A case demonstrating the clinical benefit of next-generation sequencing in sarcoma.

BACKGROUND: Inflammatory myofibroblastic tumors (IMTs) are rare mesenchymal soft tissue sarcomas that often present diagnostic challenges due to their wide and varied morphology. A subset of IMTs have fusions involving ALK or ROS1. The role of next-generation sequencing (NGS) for classification of unselected sarcomas remains controversial. METHODS AND RESULTS: We report a case of a metastatic sarcoma in a 34-year-old female originally diagnosed as an unclassified spindle cell sarcoma with myofibroblastic differentiation and later reclassified as IMT after NGS revealed a TFG-ROS1 rearrangement. Histologically, the neoplasm had spindle cell morphology with a lobulated to focally infiltrative growth pattern with scant inflammatory cell infiltrate. Immunohistochemistry demonstrated focal desmin and variable smooth muscle actin staining but was negative for SOX10, S100, and CD34. Fluorescence in situ hybridization was negative for USP6 or ALK gene rearrangements. NGS revealed a TFG-ROS1 rearrangement and the patient was treated with crizotinib with clinical benefit. CONCLUSIONS: We discuss the role of NGS as well as its potential benefit in patients with unresectable, ALK-negative metastatic disease. Considering this case and previous literature, we support the use of NGS for patients requiring systemic treatment.

Evaluation of Myo-Intimal Media Thickness and Atheromatous Plaques in People Living with HIV from the Archiprevaleat Cohort vs. HIV-Negative Subjects.

BACKGROUND: Antiretroviral therapy has allowed a clear improvement in prognosis for HIV patients, but metabolic problems, such as dyslipidemia, remain. This can lead to the development of atheromatous plaques. Our study aims to evaluate whether HIV-positive (HIV+) patients show higher myo-intimal media thickness (IMT) and atheromatous plaques compared to HIV-negative (HIV-) patients. METHODS: To evaluate the association between HIV infection in experienced patients and vascular pathology, we performed a cross-sectional study, observing 1006 patients, 380 HIV+ enrolled in the Archiprevaleat cohort, and 626 HIV- as a control group. All patients underwent a Doppler scan of the supra-aortic vessels. We compared the prevalence of IMT > 1.0 mm and plaques in the two groups. RESULTS: Patients in the HIV+ group were younger than those in the HIV- group, with a lower prevalence of hypertension and diabetes and higher dyslipidemia. The prevalence of plaques in strata of age was higher in the HIV+ group than in the HIV- group and was associated with the length of ART exposure. CONCLUSIONS: Our cross-sectional, retrospective study shows that HIV+ experienced patients are at greater risk of IMT and atheromatous plaques compared to HIV-. The risk is associated with being HIV+ and with the length of ART exposure. This finding may be useful in preventing cardiovascular risk.

Inflammatory Myofibroblastic Tumor of the Esophagus and Stomach Successfully Treated With ALK Inhibitor in a Pediatric Patient: A Case Report and Concise Review of Literature.

An inflammatory myofibroblastic tumor (IMT) is a rare mesenchymal neoplasm of borderline malignant potential. Nearly half of all IMTs have rearrangement of anaplastic lymphoma kinase (ALK) locus on chromosome 2p23 which can be treated with targeted therapy. Herein, we describe an unusual presentation of IMT involving an anatomical region rarely implicated in this disease process. A 15-year-old male patient came to the ER with dysphagia and coffee ground emesis. On esophagogastroscopy, a nodular luminal obstructing 30 × 50 mm mass in the lower esophagus was found, which was continuous with a large, partially circumferential gastric mass extending from the mid-body to the proximal antrum. Biopsies from esophageal and gastric masses revealed submucosal lesions composed of cytologically bland spindle and epithelioid cells, intermingled with inflammatory infiltrate, for which several immunohistochemical (IHC) stains were performed. The molecular study demonstrated ATIC::ALK fusion. Based on morphological, IHC, and molecular study findings, the diagnosis of ALK-positive IMT was rendered. Because surgical excision was deemed infeasible, the patient was started on ALK-inhibiting therapy with crizotinib. The patient responded well with no evidence of residual or recurrent disease on follow-up imaging or surveillance esophagogastroduodenoscopy. Crizotinib was ultimately discontinued after 10 months of therapy, and the patient continues to undergo surveillance imaging for monitoring of disease burden.