The effects of pyrrolo[1,2-b][1,2,5]benzothiadiazepines in MEC1 cells.

Chronic Lymphocytic Leukemia (CLL) is the most common adult leukemia and is currently incurable. To expand the therapeutic armamentarium, we investigated antitumor activity of pyrrolo[1,2-b][1,2,5]benzothiadiazepine (PBTDs) in MEC1 cells. We found that PBTD (RS2778) treatment enhanced the activation of pro-apoptotic members, such as caspase-9, 3, poly (ADP-ribose) polymerase (PARP), and bax, but suppressed the activation of anti-apoptotic molecule BCL-2 in these cells. Furthermore, PBTD (RS2778)-induced autophagic cell death was verified by LC3-II conversion, and upregulation of Beclin-1 and ATG5. In addition, such compound impeded hyper phosphorylation of AKT as were determined by Western blot. In summary, PBTD (RS2778) inhibited viability and induced multiple cellular events including apoptosis, autophagic cell death, in human MEC1 cells. This distinct activity of PBTD (RS2778) against these cells suggests potential for PBTDs as a therapeutic agent for treatment of CLL.

Colo-colic intussusception in an adult caused by lipoma: Case report of a rare condition.

This report describes the case of a 56-year-old woman who presented at the emergency room with a 3-week history of severe, intermittent abdominal pain. A CT scan revealed colo-colic intussusception caused by a large, substenosing mass with predominant adipose density. Subsequent endoscopic examination with biopsy revealed a necrotic tissue covering the mass, without definitive histological characterization. A second biopsy led to the extremely rare diagnosis of colo-colic lipoma. While intussusception is rare in adults, it's important to consider it as a differential diagnosis, especially when presenting with abdominal pain and signs of bowel obstruction. Timely diagnosis and appropriate treatment are essential to prevent complications.

Efficacy of High-dose Liraglutide 3.0 mg in Patients with Poor Response to Bariatric Surgery: Real-world Experience and Updated Meta-analysis.

PURPOSE: Poor response to bariatric surgery, characterized by insufficient weight loss (IWL) or weight regain (WR), poses a significant challenge in obesity treatment. This study aims to assess the effectiveness of liraglutide in addressing this issue. MATERIALS AND METHODS: A retrospective, multicenter cohort study investigated the impact of liraglutide 3 mg on weight loss in adults with suboptimal responses or weight regain after bariatric surgery (BS). Additionally, a systematic review and meta-analysis were conducted for a comprehensive evaluation. RESULTS: A total of 119 patients (mean age 41.03 ± 11.2 years, 71.4% female) who experienced IWL or WR after BS received pharmacologic therapy with liraglutide 3 mg. Mean percent weight loss in the entire cohort was 5.6 ± 2.6% at 12 weeks and 9.3 ± 3.6% at 24 weeks with a significant reduction in waist circumference (p < 0.0001). No serious side effects were reported. A meta-analysis, utilizing the fixed effect model with the metafor package in R, included 6 and 5 papers for the change in body weight and BMI after liraglutide treatment, respectively. The analysis demonstrated a considerable reduction in body weight (7.9; CI - 10.4; - 5.4, p < 0.0001) and BMI (3.09; CI 3.89; - 2.28, p < 0.0001). CONCLUSION: Liraglutide 3 mg emerges as a viable option for significant weight loss in patients experiencing IWL or WR after BS. Its inclusion in a multimodal, sequential obesity treatment approach proves promising.

High-dose liraglutide improves metabolic syndrome in poor responders to bariatric surgery.

Background: Bariatric surgery (BS) represents the most effective therapy for obesity class III, or class II with at least one weight-related comorbidity. However, some patients have insufficient weight loss or clinically relevant weight regain after a successful primary procedure. This study aimed to assess the efficacy of liraglutide treatment on weight loss, body composition and improvement of metabolic syndrome (MS) in patients defined as poor responders after BS. Methods: The study involved 59 non-diabetic adults with obesity (M/F: 17/42, age: 38.6 ± 11.8 years, BMI 38.3 ± 5.5 kg/m2) who had been treated with BS and experienced a poor response, categorized as either IWL (insufficient weight loss) or WR (weight regain). All patients were prescribed pharmacological therapy with liraglutide and attended nutritional counseling. Anthropometric and clinical measurements, body composition and the presence of MS defined according to the ATP-III classification were evaluated before starting liraglutide and after 24 weeks of treatment. Results: After 24 weeks of treatment with liraglutide, the mean weight loss was 8.4% ± 3.6% with no difference between gender, bariatric procedure, or type of poor response (IWL or WR). A significant decrease in fat mass, free-fat mass and total body water was documented. After 24 weeks, patients presented significantly lowered fasting glucose, total cholesterol, triglycerides, AST and ALT. The prevalence of MS was reduced from 35% at baseline to 1.6% after 24 weeks. No patients discontinued the treatment during the study. Conclusion: In patients who experience poor response after BS, liraglutide is well tolerated and promotes significant weight loss, ameliorates cardiometabolic comorbidities, and reduces the prevalence of MS.

Blood derived stem cells: an ameliorative therapy in veterinary ophthalmology.

Stem cell technology has evoked considerable excitement among people interested in the welfare of animals, as it has suggested the potential availability of new tools for several pathologies, including eye disease, which in many cases is considered incurable. One such example is ulcerative keratitis, which is very frequent in horses. Because some of these corneal ulcers can be very severe, progress rapidly and, therefore, can be a possible cause of vision loss, it is important to diagnose them at an early stage and administer an appropriate treatment, which can be medical, surgical, or a combination of both. The therapeutic strategy should eradicate the infection in order to reduce or stop destruction of the cornea. In addition, it should support the corneal structures and control the uveal reaction, and the pain associated with it, in order to minimize scarring. In this study, we address how stem cells derived from peripheral blood can be used also in ophthalmological pathologies. Our results demonstrate that this treatment protocol improved eye disease in four horse cases, including corneal ulcers and one case of retinal detachment. In all cases, we detected a decrease in the intense inflammatory reaction as well as the restoration of the epithelial surface of the central cornea.

Jejunal volvulus within an inguinal hernia sac like as an extremely rare cause of acute mechanical gastrointestinal obstruction in adults: First literature report.

INTRODUCTION AND IMPORTANCE: Small bowel volvulus (SBV) represents a rare and life-threatening cause of gastrointestinal obstruction among adults. SBV can be classified as primary and secondary subtypes. Preoperative diagnosis of SBV is a challenge because of the absence of pathognomonic clinical, radiographic and laboratory findings. Surgery represents the correct treatment of SBV. CASE PRESENTATION: A 69-year-old Caucasian male presented to the Emergency Department with a two-day history of abdominal pain, inability to pass gas or stool, nausea, vomiting. Physical examination revealed abdominal distension, generalized abdominal pain without guarding or rebound tenderness, a partially reducible and painless right inguinal hernia. Laboratory tests reported neutrophilic leukocytosis. Abdominal computed tomography revealed massive gastroduodenal dilatation with pneumoperitoneum and small bowel loops in the right inguinal sac. The patient underwent exploratory laparotomy: a jejunal volvulus (JV) located within the right inguinal hernia sac, causing gastrointestinal obstruction, was devolvulated and a right prosthetic inguinal hernia repair was also performed. The patient was discharged on the 10th postoperative day. CLINICAL DISCUSSION: Secondary SBV is due to any congenital or acquired lesions and rarely occurs among adults in Western countries. This is the first literature report of a JV located within an inguinal hernia sac causing gastrointestinal obstruction. CONCLUSION: Secondary JV represents an extremely rare abdominal emergency necessitating early diagnosis to prevent the development of intestinal ischemia, bowel necrosis and peritonitis. Diagnosis of JV needs a high index of suspicion and may be facilitated by imaging, often it is made intraoperatively. Surgery represents the appropriate treatment of JV.

Granular cell tumor of the cecum: Case report of mini invasive surgical resection and review of the literature.

INTRODUCTION AND IMPORTANCE: Granular Cell Tumor (GCT) is a rare lesion with unclear histogenesis, predominantly described as a skin lesion. Visceral localization of GCT is even more rare with few cases reported in the literature. Nowadays GCT guidelines are not available. CASE PRESENTATION: A 45-year-old Caucasian woman was visited in our surgical department for significant weight loss (about 30 kg) during the previous 6 months. Colonoscopy showed a caecal polypoid lesion that was resected with a diatermic loop and classified as GCT. Microscopically, the neoplasm partially involved the mucosa and diffusely the submucosa, extending to the endoscopic resection margins. Because of the high risk of perforation during endoscopic radicalisation attempt, the patient underwent ileocecal resection. The postoperative course was uneventful. CLINICAL DISCUSSION: GCT is a rare soft tissue neoplasm probably deriving from Schwann cells. The main treatment for GCT is an endoscopic mucosal/submucosal resection. Nevertheless, a radicalization of the lesion through a surgical attempt should be preferred when the endoscopic procedure is linked to a high risk of perforation. It is important to distinguish GCT from other polypoid lesions of the colon, due to its malignant potential (about 2%) and its relapsing capacity when margins are involved. CONCLUSION: GTC is a rare neoplasm and as its diagnosis is made only histologically, it should be included in differential diagnosis of colonic polypoid lesions. Surgery can be considered the best choice when an endoscopic attempt of GCT lesions is linked to a high risk of colon perforation.

Complicated Littre's umbilical hernia with normal Meckel's diverticulum: A case report and review of the literature.

INTRODUCTION AND IMPORTANCE: A Littre's hernia (LH) is defined by the presence of Meckel's diverticulum (MD) in any kind of hernia sac. Preoperative diagnosis of LH is a challenge because of its rarity and the absence of specific radiological findings and clinical presentation. Surgery is the appropriate treatment of complicated LH that is an extremely rare condition with approximately 50 cases reported in the literature over the past 300 years. CASE PRESENTATION: A 46-year-old Caucasian female was admitted to the Emergency Department with a two-day history of abdominal pain. Physical examination revealed an irreducible and painfull mass in umbilical region. Abdominal computed tomography scan showed the protrusion of greater omentum and small bowel loop through the umbilical ring. Laboratory tests were unremarkable. After diagnosis of strangulated umbilical hernia, the patient underwent exploratory laparotomy: the irreducible umbilical hernial sac was opened with presence of incarcerated and strangulated omentum and uncomplicated MD. Resection of incarcerated and ischemic greater omentum alone was performed. The postoperative course of patient was uneventful. CLINICAL DISCUSSION: Meckel's diverticulum (MD) is a vestigial remnant of the omphalomesenteric duct, representing the most common congenital malformation of the gastrointestinal tract. Preoperative diagnosis of LH is very difficult and surgery represents the correct treatment of complicated LH. CONCLUSION: LH represents an extremely rare complication of MD difficult to diagnose and suspect because of the lack of specific radiological findings and clinical presentation. Surgery represents the appropriate treatment of abdominal wall hernias and complicated MD.

Pyrrolo[1,2-b][1,2,5]benzothiadiazepines (PBTDs) exert their anti-proliferative activity by interfering with Akt-mTOR signaling and bax:bcl-2 ratio modulation in cells from chronic myeloid leukemic patients.

In our study we found that pyrrolo[1,2-b][1,2,5]benzothiadiazepines (PBTDs) mediated apoptosis in primary leukemia cells from 27 chronic myelogenous leukemia (CML) patients at onset through the activation of the caspase-9 and -3, and cleavage of poly (ADP-ribose) polymerase (PARP). The bax:bcl-2 ratio was increased as a consequence of down-regulation of bcl-2 and up-regulation of bax proteins in response to treatment with PBTDs. In addition, PBTDs were able to induce cell death in primary leukemia cells derived from 23 CML-chemoresistant patients. Furthermore, the effects of PBTDs on the Akt-mTOR (mammalian target of rapamycin) pathway were determined by Western blot. PBTDs possessed inhibitory activity against mTOR and also impeded hyper-phosphorylation of Akt as a feedback of inhibition of mTOR by rapamycin. The results presented in this study demonstrate that we have identified the PBTDs as restoring the apoptotic pathways both in primary leukemia cells derived from CML patients at onset and in primary leukemia cells derived from CML-chemoresistant patients, thus showing their ability to undergo apoptosis. These compounds constitute a promising therapeutic approach for patients with leukemia. They provide the basis for new strategies for an additional anticancer drug in leukemia therapies, especially when conventional ones fail.

The effect of marathon on mRNA expression of anti-apoptotic and pro-apoptotic proteins and sirtuins family in male recreational long-distance runners.

BACKGROUND: A large body of evidence shows that a single bout of strenuous exercise induces oxidative stress in circulating human lymphocytes leading to lipid peroxidation, DNA damage, mitochondrial perturbations, and protein oxidation.In our research, we investigated the effect of physical load on the extent of apoptosis in primary cells derived from blood samples of sixteen healthy amateur runners after marathon (a.m.). RESULTS: Blood samples were collected from ten healthy amateur runners peripheral blood mononuclear cells (PBMCs) were isolated from whole blood and bcl-2, bax, heat shock protein (HSP)70, Cu-Zn superoxide dismutase (SOD), Mn-SOD, inducible nitric oxide synthase (i-NOS), SIRT1, SIRT3 and SIRT4 (Sirtuins) RNA levels were determined by Northern Blot analysis. Strenuous physical load significantly increased HSP70, HSP32, Mn-SOD, Cu-Zn SOD, iNOS, GADD45, bcl-2, forkhead box O (FOXO3A) and SIRT1 expression after the marathon, while decreasing bax, SIRT3 and SIRT4 expression (P < 0.0001). CONCLUSION: These data suggest that the physiological load imposed in amateur runners during marathon attenuates the extent of apoptosis and may interfere with sirtuin expression.

Evaluation of Ultrasound-guided 8-Gauge Vacuum-assisted Excision System for the Removal of US-detectable Breast Lesions.

AIM: To assess the ability of ultrasound (US)-guided vacuum-assisted breast excision (VAE) to remove Breast Imaging Reporting and Data System (BI-RADS) ≥3 breast lesions in order to analyze US features most frequently associated with complete excision. MATERIALS AND METHODS: A total of 266 BI-RADS ≥3 lesions without microcalcifications underwent US-VAE. US-VAE and gold standard pathological results were compared. US features of lesions were analyzed. RESULTS: The complete excision rate was 93.61%; the VAE agreement rate was 99.62%. Circumscribed margins, regular shape, parallel orientation, and the absence of posterior features were favorable US features associated with complete excision. Lesions completely excised were: BI-RADS 3 ≤21.10 mm and BI-RADS 4 ≤18.70 mm with one unfavorable US characteristic, and BI-RADS 4 lesions ≤13.5 mm with two unfavorable US features hindered complete removal. Two atypical ductal hyperplasias (<10 mm, one unfavorable feature) and eight ductal carcinomas in situ (≤8.7 mm, one/two unfavorable features) were completely removed. CONCLUSION: US-VAE is highly accurate for diagnostic purpose and, in some cases, highly successful for complete lesion excision. This success also depends on the US characteristics and size of the lesion.

MR imaging-guided vacuum assisted breast biopsy: Radiological-pathological correlation and underestimation rate in pre-surgical assessment.

BACKGROUND: Magnetic Resonance(MR) guided percutaneous procedures(MRgVABB) have been developed and largely employed to reduce the need of surgical biopsies for suspicious lesions which can be detected only by MR(MR-only lesion). The present study aims to investigate correlation between imaging, histological features of MRgVABB and surgical specimens of MR-only lesions. METHODS: We retrospectively enrolled 56 patients with a total of 61 lesions. Each finding was defined as Mass-Enhancement(ME) or Non-ME(NME) and classified according to BI-RADS. MRgVABB and surgical data were collected. Concordance between MR, MRgVABB and open biopsy was calculated. Underestimation Rate(UR) of MRgVABB with surgery was obtained. RESULTS: B2 and B5b lesions were statistically associated with NME and ME, respectively. No statistical association was found to B3 nor to B5a with radiological features. UR was 10 %; underestimated lesions were strongly associated with the presence of a ME on MR imaging. Moreover, B3 lesions are associated with higher UR. CONCLUSION: Radiological features should influence patient management aiming to construct a correct diagnostic and therapeutic plan. When MR is prescribed for breast cancer staging for ME-MR-only lesions, we suggest surgical open biopsy instead of MRgVABB when upfront surgery is the treatment of choice.

Heat-shock pretreatment inhibits sorbitol-induced apoptosis in K562, U937 and HeLa cells.

The aim of this study was to determine whether heat-shock pretreatment exerted a protective effect against sorbitol-induced apoptotic cell death in K562, U937 and HeLa cell lines and whether such protection was associated with a decreased cytochrome c release from mithocondria and a decreased activation of caspase-9 and -3. Following heat-shock pretreatment (42 +/- 0.3 degrees C for 1 hr), these cell lines were exposed to sorbitol for 1 hr. Apoptosis was evaluated by DNA fragmentation, whereas caspase-9,-3 activation, cytochrome c release and heat-shock protein70 (HSP70) were assayed by Western Blot. Sorbitol exposure-induced apoptosis in these different cell lines with a marked activation of caspase-9 and caspase-3, whereas heat-shock pretreatment before sorbitol exposure, induced expression of HSP70 and inhibited sorbitol-mediated cytochrome c release and subsequent activation of caspase-9 and caspase-3. Similarly, overexpression of HSP70 in the three cell lines studied prevented caspase-9 cleavage and activation as well as cell death. Furthermore, we showed that the mRNA expression of iNOS decreased during both the heat-shock treatment and heat-shock pretreatment before sorbitol exposure. By contrast, the expression of Cu-Zn superoxide dismutase (SOD) and Mn-SOD proteins increased during heat-shock pretreatment before sorbitol exposure. We conclude that, heat-shock pretreatment protects different cell lines against sorbitol-induced apoptosis through a mechanism that is likely to involve SOD family members.

Right-sided aortic arch with mirror image branching and situs solitus: a case of a 79 years old woman.

Right aortic arch with mirror image branching (RAMI) is a rare congenital defect of the aorta. The exact incidence of RAMI in the general population is unclear. In RAMI the first branch arising from the arch is the left innominate artery, followed by the right carotid artery and right subclavian arteries. We report a case of an adult female patient with RAMI discovered as an incidental finding during radiological investigations for suspected pulmonary embolism in emergency department. No other congenital malformations were reported. It is important to recognize congenital variants of the aortic arch, as they can have relevant implications for patients' prognosis and management. Therefore, being aware of these conditions is key to avoid any mistakes or surgical and endovascular complications.

Internal jugular vein agenesis: a rare vascular abnormality and incidental finding. A case of internal jugular vein agenesis in a 52-years old male.

We report a case of vascular malformation arising from internal jugular vein discovered during radiological investigations for restaging of metastatic colon carcinoma of an adult male patient. Congenital absence of internal jugular vein is extremely uncommon. These developmental anomalies in general population are seen in about 0.05%-0.25%. The awareness of these vascular anomalies is extremely important to avoid unsafe complications, primarily in oncological patients, whom usually require the incannulation of neck veins for diagnostic procedures or intravenous therapy administration.

Probably Benign Breast Nodular Lesions (BI-RADS 3): Correlation between Ultrasound Features and Histologic Findings.

The purpose of this retrospective study was to determine the validity of the BI-RADS system in ultrasound findings assigned to BI-RADS 3 category, using cytologic and histologic results as a benchmark. Our study population consisted of 122 ultrasound nodular lesions in 122 women who underwent fine-needle aspiration cytology and biopsy for probably benign lesions (Breast Imaging Reporting and Data System [BI-RADS] category 3). Contrary to what was previously reported in the literature (risk of malignancy of BI-RADS 3 <2%), malignancy was the outcome in seven of 122 cases (5.7%). Our study also found that the presence of a cellular component with a mobile fluid-fluid level in a cystic lesion and small (<3 mm) anechoic components in solid lesions is not always an indication of benignity. Our experience seems to indicate the need to consider the presence of non-homogeneous echoes in the corpuscular cyst and solid nodular lesions with cystic components as suspicious, especially in lesions with large dimensions. Therefore it would be necessary to conduct further studies to establish a dimensional criterion in the assessment of the malignant nature of the mentioned lesions. The management of probably benign nodular lesions should not only be guided by BI-RADS classification; it is also necessary to include clinical and anamnestic data and apply a multidisciplinary approach to select cases that require histologic verification instead of the usual follow-up.

The interference of rosmarinic acid in the DNA fragmentation induced by osmotic shock.

The induction of cell death in human erythroleukemic cells (K562) by sorbitol shows the typical apoptotic changes in ultrastructural morphology, including blebbing, chromatin condensation and nuclear membrane breakdown. Using a cytofluorimetric approach, we found that sorbitol induced production of reactive oxygen species (ROS) followed by DNA fragmentation in leukemic cells. In this study, we investigated effect of curcumin and rosmarinic acid on cell viability in three different cell lines: erythroleukemia K562, papillary NPA, and anaplastic ARO thyroid cancers. Curcumin was able to induce apoptosis in a concentration- and time dependent manner in three cell lines, while rosmarinic acid was less effective on this process. To examine this possibility in cellular system, this study evaluated the capacities of both compounds acting as antioxidant inhibiting sorbitol-induced apoptosis. K562, NPA and ARO cells were pre-incubated with 25 microM rosmarinic acid to allow the uptake and then the cell lines were treated with 1 M sorbitol. Afterwards, the cells were subjected to agarose gel electrophoresis to assess the DNA fragmentation. In conclusion, the antioxidant activity of rosmarinic acid is able to inhibit sorbitol-induced apoptosis.

PYRROLO[1,2-b][1,2,5]BENZOTHIADIAZEPINES (PBTDs) induce apoptosis in K562 cells.

BACKGROUND: The objective of this study was to gain insight into the molecular mechanism of induced cell death (apoptosis) by PYRROLO [1,2-b][1,2,5]BENZOTHIADIAZEPINES (PBTDs) series compounds, using human (K562) cells as a model. METHODS: We focused our attention on some members of the PBTDs family to test their potential apoptotic activity in K562 cells. Important apoptotic activity was demonstrated, as evidenced by the concentration and percentage of cell death quantified by measuring PI-uptake by flow cytometry, and DNA fragmentation analyzed by agarose gel electrophoresis, generating a characteristic ladder pattern of discontinuous DNA fragments. The expression of Bcl-2 family was tested using western blotting and transfection method. RESULTS: PBTDs-mediated suppression of K562 cell proliferation was induced by apoptosis characterized by the appearance of DNA fragmentation and was associated with the poly(ADP-ribose)polymerase (PARP) cleavage. PBTD-1 and -3 treatment resulted in caspase-3 activation through down-regulation of Bcl-2 and up-regulation of Bax. Furthermore, we used K562/vector and K562/bcl-2 cells, which were generated by transfection of the cDNA of the Bcl-2 gene. As compared with K562/vector, K562/Bcl-2 cells exhibited a 4-fold greater expression of Bcl-2. Treatment with 10 muM PBTD-1 and -3 for 24 h produced morphological features of apoptosis and DNA fragmentation in K562/vector cells, respectively. In contrast, PBTD-1 and -3-induced caspase-3 activation and apoptosis were inhibited in K562/Bcl-2. Furthermore, Bcl-2 overexpressing cells exhibited less cytocrome c release during PBTDs-induced apoptosis. CONCLUSION: These results indicate that PBTDs effectively induce apoptosis of K562 leukemia cells through the activation of caspase cascades. In addition, these findings indicate that Bcl-2 inhibits PBTD-1 and -3 induced-apoptosis via a mechanism that interferes with cytocrome c release, and the activity of caspase-3, which is involved in the execution of apoptosis.

Pyrrolo[1,2-b][1,2,5]benzothiadiazepines (PBTDs): A new class of agents with high apoptotic activity in chronic myelogenous leukemia K562 cells and in cells from patients at onset and who were imatinib-resistant.

Pyrrolo[1,2-b][1,2,5]benzothiadiazepine 5,5-dioxides (PBTDs) induced apoptosis in human BCR-ABL-expressing leukemia cells. The apoptotic activity was also observed in primary leukemic blasts, obtained from chronic myelogenous leukemia (CML) patients at onset or from patients in blast crisis and who were imatinib-resistant. Compounds 5 and 14 induced apoptosis before BCR-ABL protein expression and tyrosin phosphorylation were affected and activated different caspases in the apoptotic pathway. PBTDs are a new class of valid candidates for the treatment of CML.