Sirtuins family as a target in endothelial cell dysfunction: implications for vascular ageing.

The vascular endothelium is a protective barrier between the bloodstream and the vasculature that may be disrupted by different factors such as the presence of diseased states. Diseases like diabetes and obesity pose a great risk toward endothelial cell inflammation and oxidative stress, leading to endothelial cell dysfunction and thereby cardiovascular complications such as atherosclerosis. Sirtuins are NAD+-dependent histone deacetylases that are implicated in the pathophysiology of cardiovascular diseases, and they have been identified to be important regulators of endothelial cell function. A handful of recent studies suggest that disbalance in the regulation of endothelial sirtuins, mainly sirtuin 1 (SIRT1), contributes to endothelial cell dysfunction. Herein, we summarize how SIRT1 and other sirtuins may contribute to endothelial cell function and how presence of diseased conditions may alter their expressions to cause endothelial dysfunction. Moreover, we discuss how the beneficial effects of exercise on the endothelium are dependent on SIRT1. These mainly include regulation of signaling pathways related to endothelial nitric oxide synthase phosphorylation and nitric oxide production, mitochondrial biogenesis and mitochondria-mediated apoptotic pathways, oxidative stress and inflammatory pathways. Sirtuins as modulators of the adverse conditions in the endothelium hold a promising therapeutic potential for health conditions related to endothelial dysfunction and vascular ageing.

Long-term clinical outcomes of male breast cancer patients treated with curative intent by trimodality therapy at an academic university hospital in India.

INTRODUCTION: Male breast cancer is rare and accounts for less than 1% of all breast cancer cases worldwide. METHODS: This retrospective cohort study included all patients of invasive male breast cancer treated with curative intent by a trimodality approach via a multidisciplinary team at an academic university hospital in India between 2009 and 2023. Records were identified from a prospectively maintained database. Clinicopathological parameters, treatment details and survival were recorded and analysed. RESULTS: Thirty-four patients were included. The median (IQR) age was 55(44-63) years. Most patients were overall stage III (74%) and node positive (79%) with Scarff-Bloom-Richardson grade II (50%). Twenty-five patients (73%) were oestrogen receptor (ER) positive. Lymphovascular space invasion (LVSI) and perineural invasion (PNI) were present in 62% and 21% of patients, respectively. The most common chemotherapy timing was adjuvant (53%) followed by neoadjuvant (41%), and the most commonly used regimen consisted of a combination of doxorubicin-cyclophosphamide followed by a taxane (53%). Most (85%) patients underwent a mastectomy, five patients underwent breast conservation. All patients received radiotherapy to a dose of 42.6 Gy in 16 fractions, followed by a tumour bed boost for those undergoing breast conservation. At a median follow-up of 70 months (range 10-159 months), the five and ten-year overall survival was 91% and 58%, and the five-year disease-free survival (DFS) was 67%. The median DFS was 72 months. On univariate analysis, the tumour sub-type (Luminal versus TNBC) significantly predicted DFS (P = 0.03 log-rank). CONCLUSION: Breast cancer in males has a high incidence of node positivity, ER positivity and LVSI. Even with advanced stages at presentation, trimodality therapy in a multidisciplinary setting offers good long-term outcomes.

Platelet CD36 surface expression levels affect functional responses to oxidized LDL and are associated with inheritance of specific genetic polymorphisms.

CD36 modulates platelet function via binding to oxidized LDL (oxLDL), cell-derived microparticles, and thrombospondin-1. We hypothesized that the level of platelet CD36 expression may be associated with inheritance of specific genetic polymorphisms and that this would determine platelet reactivity to oxLDL. Analysis of more than 500 subjects revealed that CD36 expression levels were consistent in individual donors over time but varied widely among donors (200-14,000 molecules per platelet). Platelet aggregometry and flow cytometry in a subset of subjects with various CD36 expression levels revealed a high level of correlation (r² = 0.87) between platelet activation responses to oxLDL and level of CD36 expression. A genome-wide association study of 374 white subjects from the Cleveland Clinic ASCLOGEN study showed strong associations of single nucleotide polymorphisms in CD36 with platelet surface CD36 expression. Most of these findings were replicated in a smaller subset of 25 black subjects. An innovative gene-based genome-wide scan provided further evidence that single nucleotide polymorphisms in CD36 were strongly associated with CD36 expression. These studies show that CD36 expression on platelets varies widely, correlates with functional responses to oxLDL, and is associated with inheritance of specific CD36 genetic polymorphisms, and suggest that inheritance of specific CD36 polymorphisms could affect thrombotic risk.

An audit of uterine perforation and its effect on the final outcome in an academic research medical center: An optimized balance between overall treatment time and medical crisis.

Purpose: Intra-cavitary brachytherapy is an integral component of cervical cancer management, and uterine perforation is the most significant complication, which may lead to prolonged overall treatment time and decreased local control in these patients. Material and methods: A retrospective analysis of cervical cancer patients who completed radiotherapy (external beam radiotherapy and brachytherapy) in our department was conducted to determine the incidence, effect on overall treatment time, and final outcome in patients with uterine perforation during brachytherapy procedure. Results: Among 55 women, of the 398 applications, 85 (21.36%) resulted in uterine perforation. Out of these 85 applications, treatment time was extended among 3 (3.5%) applications only, as re-insertion was done nearly after one week, while the remaining 82 (96.5%) applications were completed in time. At the time of analysis, the median follow-up was 12 months, and 32 patients were disease-free, 3 had distant metastatic disease, 2 had residual disease, and 18 were lost to follow-up. Conclusions: In our study, uterine perforation incidence was found to be comparable with other centers worldwide. In asymptomatic and uncomplicated uterine perforation, treatment can be continued with computer-based optimized treatment plans without loading a specific dwell position and without affecting overall treatment time.

External Beam Radiotherapy Interdigitated with High Dose Rate(HDR) Intracavitary Brachytherapy versus External Beam Radiotherapy followed by Sequential HDR Intracavitary Brachytherapy for Locally Advanced Carcinoma Cervix-Randomized Control Study.

BACKGROUND: In cervical cancer treatment, overall treatment time (OTT) is an important prognostic factor. This study compares the clinical outcomes when High-Dose-Rate Intracavitary-Brachytherapy(HDR-ICRT) is interdigitated with external beam radiotherapy(EBRT) versus sequential HDR-ICRT after EBRT in the treatment of locally advanced carcinoma cervix. METHODS: Histologically confirmed carcinoma cervix patients [FIGO Stage IIB-IVA (except IIIC-2)] were included and randomized into two groups. The study group received EBRT 50Gy in 25 fractions with interdigitated HDR-ICRT 7Gy per fraction weekly for three fractions starting after completion of 3 weeks of EBRT or as soon as cervical os became negotiable thereafter. Patients in the control group received EBRT 50Gy in 25 fractions with sequential HDR-ICRT 7Gy per fraction weekly for three fractions starting one week after completion of EBRT. All patients were regularly followed up during and after radiotherapy for local toxicity and disease control. RESULTS: This study enrolled 102 patients; 51 in each arm. Median OTT in study and control arm were 46 and 60 days, respectively. Median follow-up duration was 24 months (two years). Loco-regional control after two years of follow-up was 84.31 % and 72.54% of patients in study arm control arm respectively (p-value 0.148). Two (3.92%) patients from study arm and eight (15.68%) from control arm had residual disease. Two patients in study arm and one from control arm had local recurrence. Two patients from study arm three patients from control arm developed distant metastases. RTOG mucosal grade III acute mucosal toxicity in either arm. Cervical-os negotiability was limiting factor for interdigitated HDR-ICRT. CONCLUSIONS: Interdigitated HDR-ICRT with EBRT may give local control with manageable toxicities as compared to sequential HDR-ICRT, with the advantage of significant reduction in OTT.
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Comparative Study of Dysphagia-optimized Intensity Modulated Radiotherapy (Do-IMRT) and Standard Intensity Modulated Radiotherapy (S-IMRT) and Its Clinical Correlation in Head and Neck Cancer Patients.

OBJECTIVE: Dosimetric sparing of critical swallowing structures like constrictor muscles and larynx can lead to improved functional outcomes in head and neck cancer patients treated by chemoradiation. METHODS: A total of 50 Patients with newly diagnosed, biopsy proven AJCC stage II-IV head and neck squamous cell cancers (HNSCC) were prospectively studied. 25 patients were randomized in each arm of Dysphagia-optimized Intensity Modulated Radiotherapy (Do-IMRT) arm and Standard Intensity Modulated Radiotherapy (SIMRT) arm. Additional dose constraints were applied to the dysphagia/aspiration at risk structures (DARS) in Do-IMRT arm. The impact of using Do-IMRT was assessed by the difference in mean scores of MD Anderson Dysphagia Inventory (MDADI), University of Washington-Quality of Life (UW-QOL), and 100 ml Water Swallow Test (WST). RESULTS: Patients in both arms showed significant (P <0.01 or P < 0.001) improvement in MDADI (global and composite), UW-QOL and Water Swallow Test scores. However, the improvements were found significantly higher in Do-IMRT as compared to S-IMRT. Significant improvements i.e. mean change from baseline to 12 months (P <0.05 or P <0.01 or P <0.001) were 19. 2, 8.6, 14.3, 7.4, 18.6 and 22.0%  higher respectively in Do-IMRT as compared to S-IMRT  in MDADI global and composite scores, UW-QOL swallowing scores, and 100 ml Water Swallow  (swallowing volume, swallowing capacity and swallowing speed)  test scores. CONCLUSION: The Do-IMRT improves swallowing functions compared to S-IMRT in HNSCC patients treated with radical chemoradiation.

Platelet CD36 mediates interactions with endothelial cell-derived microparticles and contributes to thrombosis in mice.

CD36 is a scavenger receptor that binds multiple ligands, including phosphatidyl serine (PS). Although CD36(-) mice do not have a bleeding diathesis, we show here that they do have significantly prolonged thrombotic occlusion times in response to FeCl(3)-induced vascular injury. Because cell-derived microparticles (MPs) are generated in response to vascular injury and circulate in patients with prothrombotic diseases, we hypothesized that PS exposed on their surfaces could be an endogenous CD36 ligand that transmits an activating signal to platelets. We found that MPs prepared from human ECs, monocytes, or platelets or isolated from blood of normal subjects bound to platelets. Binding was not observed with platelets from CD36(-) donors and was inhibited by an anti-CD36 antibody or by blockade of exposed PS by annexin V or anti-PS IgM. Preincubation of platelets with MPs led to CD36-dependent augmentation of platelet activation in response to low doses of ADP, as assessed by measuring alpha(2b)beta(3) activation, P-selectin expression, and aggregation. Immunofluorescence confocal microscopy of murine carotid thrombi from CD36(-) mice showed a significant decrement in endothelial antigen accumulation, which suggests that CD36 plays a role in MP recruitment into thrombi. These results provide what we believe to be a novel role for CD36 in thrombosis.

Catering the Needs of Cancer Contemporary to this Contagious Corona Catastrophe: Institution Based Changes in Cancer Management and Protection Procedures.

The COVID-19 global pandemic has drastically affected the health care facility worldwide, posing unprecedented challenges in front of the caregivers. All hospitals need adopt measures to protect patients and health professionals and to safely triage patients (according to country/regional directives) for identifying those infected with coronavirus. As very few guidelines are available for care of cancer patients during COVID times, institutes have had to make their own strategies, based on their own expertise keeping in mind local directives and their effect on available resources and routine processes to offer best possible care. In this article, we have discussed in-house protocols for modification and prioritization of radical and palliative multimodality treatment of cancer patients along with our infection control measures in accordance with national and local guidelines during COVID emergency to stay safe and health. Also, the current study aims to modify cancer treatment and care during the COVID-19 pandemic adhering and fulfilling all protective measures.

A Study to Assess the Dosimetric Impact of the Anatomical Changes Occurring in the Parotid Glands and Tumour Volume during Intensity Modulated Radiotherapy using Simultaneous Integrated Boost (IMRT-SIB) in Head and Neck Squamous Cell Cancers.

BACKGROUND: Anatomical variations in head and neck cancer during IMRT leads to volume shrinkage, results in dosimetric variations in tumour and normal tissue including parotid glands, with a risk of radiation toxicities. METHODS: 30 patients with a stage II-IV head and neck squamous cell carcinoma (HNSCC) were treated with definitive IMRT-SIB and concomitant chemotherapy. Volumetric and dosimetric variations were evaluated during the period of IMRT by recalculating and obtaining dose-volume histograms of re-contoured target volumes and parotid glands on repeat CT scans taken multiple times during treatment (CT1, CT2, CT3 and CT4). RESULTS: Result showed significant (p < 0.001) mean decrease in both primary and nodal tumors volume with time whereas increase (p < 0.01 or p < 0.001) in respective V100 (%) and D2% (Gy). The mean parotid gland dose increased (p < 0.01 or p < 0.001) with time, whereas parotid gland volume and distance between plan isocenter and centre of mass of parotid glands decreased (p < 0.05 or p < 0.001) with time. Patient's mean weight and neck circumference both decrease (p < 0.001) with time whereas ECOG score increase (p < 0.001) with time. The mucosal toxicity increased significantly (p < 0.001) with time. The change in both weight and neck circumference showed significant (p < 0.001) and direct (positive correlation) association with change in parotid gland volume. CONCLUSION: If the PTV and normal anatomy are changing with time, adaptive IMRT would be beneficial radiation dose delivery where possible.

Telepathology at the Armed Forces Institute of Pathology: A Retrospective Review of Consultations From 1996 to 1997.

CONTEXT: - Telepathology is the practice of pathology at a distance, transmitting images using telecommunication methods for second opinion and/or diagnostic assistance, or for educational purposes. It may be the only means of consultation for some pathologists. OBJECTIVE: - To retrospectively review and evaluate a subset of telepathology consultations from June 1996 to March 1997, and to determine the concordance between the telepathology diagnosis of the contributor and pathologists at the Armed Forces Institute of Pathology (AFIP), Washington, District of Columbia, as well as the concordance between the telepathology diagnosis and the glass slide diagnosis, when available. DESIGN: - Photocopies of de-identified telepathology reports from the AFIP during a 15-month period between June 1996 and March 1997 were reviewed. Contributor versus telepathology diagnosis was graded as 1 (complete agreement), 2 (partial agreement), 3 (disagreement; usually a diagnosis of benign versus malignant), and deferred. Data were analyzed using descriptive statistical methods. RESULTS: - Of the 262 cases, 194 (74%) were in complete agreement with the contributor's diagnosis, 34 of 262 (13%) were in minor disagreement, and 21 of 262 (8%) were in major disagreement. Diagnoses were deferred in 5% (13 of 262) of cases. CONCLUSIONS: - Using commercial off-the-shelf technology and despite telecommunication challenges during that time, the AFIP demonstrated that telepathology could be conducted reliably.

Endothelial dysfunction in diabetes and hypertension: Role of microRNAs and long non-coding RNAs.

The vascular endothelium acts as a barrier between the blood flow and the inner lining of the vessel wall, and it functions as a filtering machinery to filter out any unwanted transfer of materials from both sides (i.e. the blood and the surrounding tissues). It is evident that diseases such as diabetes, obesity, and hypertension disturb the normal endothelial functions in humans and lead to endothelial dysfunction, which may further precede to the development of atherosclerosis. Long non-coding RNAs and micro RNAs both are types of non-coding RNAs which, in the recent years, have increasingly been studied in the pathophysiology of many diseases including diabetes, obesity, cardiovascular diseases, neurological diseases, and others. Recent findings have pointed out important aspects on their relevance to endothelial function as well as dysfunction of the system which may arise from presence of diseases such as diabetes and hypertension. Diabetes or hypertension-mediated endothelial dysfunction show characteristics such as reduced nitric oxide synthesis through suppression of endothelial nitric oxide synthase activity in endothelial cells, reduced sensitivity of nitric oxide in smooth muscle cells, and inflammation - all of which have been either shown to be directly caused by gene regulatory mechanisms of non-coding RNAs or shown to be having a correlation with them. In this review, we aim to discuss such findings on the role of these non-coding RNAs in diabetes or hypertension-associated endothelial dysfunction and the related mechanisms that may pave the way for alleviating endothelial dysfunction and its related complications such as atherosclerosis.

Evaluation of Android Smartphones for Telepathology.

BACKGROUND: In the year 2014, Android smartphones accounted for one-third of mobile connections globally but are predicted to increase to two-thirds by 2020. In developing countries, where teleconsultations can benefit health-care providers most, the ratio is even higher. This study compared the use of two Android phones, an 8 megapixel (MP) and a 16 MP phone, for capturing microscopic images. METHOD: The Android phones were used to capture images and videos of a gastrointestinal biopsy teaching set of referred cases from the Armed Forces Institute of Pathology (AFIP). The acquired images and videos were reviewed online by two pathologists for image quality, adequacy for diagnosis, usefulness of video overviews, and confidence in diagnosis, on a 5-point Likert scale. RESULTS: The results show higher means in a 5-point Likert scale for the 8 MP versus the 16 MP phone that were statistically significant in adequacy of images (4.0 vs. 3.75) for rendering diagnosis and for agreement with the reference diagnosis (2.33 vs. 2.07). Although the quality of images was found higher in the 16 MP phone (3.8 vs. 3.65), these were not statistically significant. Adding video images of the entire specimen was found to be useful for evaluating the slides (combined mean, 4.0). CONCLUSION: For telepathology and other image dependent practices in developing countries, Android phones could be a useful tool for capturing images.

Clinicopathologic study of calcifying fibrous tumor of the gastrointestinal tract: a case series.

Calcifying fibrous tumor (CFT) is a rare benign mesenchymal lesion known to arise at multiple body sites that may clinically mimic other more aggressive lesions in the gastrointestinal (GI) tract. In this study we describe the clinicopathologic findings of 28 GI tract CFTs. Tumors predominantly arose in middle-aged adults with a slight female predominance. The most commonly involved sites were small bowel and colon, followed by stomach and appendix. Tumors ranged from 0.3 to 9.3 cm (median 1.4 cm), and submucosa was the most commonly involved layer. All tumors were well circumscribed and unencapsulated. Microscopically, tumors were hypocellular and composed of spindle cells with abundant, haphazardly arranged hyalinized collagen. No necrosis and less than one mitosis per 10 HPF were identified in all cases. Calcification was present in most (81%) of the cases. All cases had lymphoplasmacytic inflammatory infiltrates either scattered throughout the lesion with occasional perivascular conglomeration or in the form of lymphoid aggregates. A lymphoplasmacytic cuff was usually present (81%). Immunostains showed variable CD34 immunoreactivity and variable numbers of IgG4-positive plasma cells. The lesional cells were negative for DOG-1, ALK-1, S100, C-kit, Sox10, Melan A, HMB45, desmin, CK7, and CK20, and showed cytoplasmic staining for ß-catenin. Follow-up information was available in 5 cases with no recurrences reported to date (mean follow-up, 3 years). CFT is a rare benign tumor that can occur in part of the GI tract and should be distinguished from other mesenchymal tumors due to its low risk of recurrence.

Interaction between IL1B gene promoter polymorphisms in determining susceptibility to Helicobacter pylori associated duodenal ulcer.

It has been speculated that IL-1 genes play a crucial role in the genetic predisposition to duodenal ulcer upon H. pylori infection by modulating the host immune response. In the present study, 310 individuals from Eastern India were subjected to a case-control study to determine the IL1B and IL1RN risk genotypes to H. pylori mediated duodenal ulcer. An analysis of genotype frequency revealed a significantly higher frequency of IL1B -511TT (NT_022135.14:g.2302610C>T), OR=4.22 (95% CI=1.8-9.4) and -31CC (NT_022135.14:g.2302130C>T), OR=2.16 (95% CI 1.12-4.15) genotypes in H. pylori-infected individuals with duodenal ulcer compared to infected individuals with normal mucosa. Moreover, the T/C haplotype of IL1B -511 and IL1B -31 loci was present in a significantly higher frequency in H. pylori-infected duodenal ulcer patients than in infected controls (OR=2.47, CI=1.27-4.8). Quantitative analysis of the mucosal IL1B mRNA revealed that among H. pylori-infected individuals, carriers of the -31CC genotype had significantly lower IL1B transcript levels than carriers of the CT (P<0.001) and TT (P<0.001) genotypes, independently of disease status. An IL1B promoter activity assay showed that the promoter with -31T had a 10-fold increase in activity compared to the one with -31C. The IL1B promoter bearing the different combinations of both polymorphic loci showed an interaction between the -511 and -31 loci. Our results show that H. pylori-infected individuals with the -31CC genotype secrete less IL1B and are susceptible to duodenal ulcers. They also suggest that the allelic interaction between the -511 and -31 polymorphic sites determines the overall strength of the IL1B promoter.

Corrigendum to "Characterization of Zebrafish von Willebrand Factor Reveals Conservation of Domain Structure, Multimerization, and Intracellular Storage".

[This corrects the article DOI: 10.1155/2012/214209.].

CD47 in the tumor microenvironment limits cooperation between antitumor T-cell immunity and radiotherapy.

Although significant advances in radiotherapy have increased its effectiveness in many cancer settings, general strategies to widen the therapeutic window between normal tissue toxicity and malignant tumor destruction would still offer great value. CD47 blockade has been found to confer radioprotection to normal tissues while enhancing tumor radiosensitivity. Here, we report that CD47 blockade directly enhances tumor immunosurveillance by CD8(+) T cells. Combining CD47 blockade with irradiation did not affect fibrosarcoma growth in T cell-deficient mice, whereas adoptive transfer of tumor-specific CD8(+) T cells restored combinatorial efficacy. Furthermore, ablation of CD8(+) T cells abolished radiotherapeutic response in immunocompetent syngeneic hosts. CD47 blockade in either target cells or effector cells was sufficient to enhance antigen-dependent CD8(+) CTL-mediated tumor cell killing in vitro. In CD47-deficient syngeneic hosts, engrafted B16 melanomas were 50% more sensitive to irradiation, establishing that CD47 expression in the microenvironment was sufficient to limit tumor radiosensitivity. Mechanistic investigations revealed increased tumor infiltration by cytotoxic CD8(+) T cells in a CD47-deficient microenvironment, with an associated increase in T cell-dependent intratumoral expression of granzyme B. Correspondingly, an inverse correlation between CD8(+) T-cell infiltration and CD47 expression was observed in human melanomas. Our findings establish that blocking CD47 in the context of radiotherapy enhances antitumor immunity by directly stimulating CD8(+) cytotoxic T cells, with the potential to increase curative responses.

Thrombospondin-1 and CD47 signaling regulate healing of thermal injury in mice.

More than 2.5 million Americans suffer from burn injuries annually, and burn management is a major public health problem. Treatments have been developed to manage wound injuries employing skin grafts, various dressings and topical and systemic agents. However, these often achieve limited degrees of success. We previously reported that targeting the interaction of thrombospondin-1 with its signaling receptor CD47 or deletion of the genes encoding either of these proteins in mice improves recovery from soft tissue ischemic injuries as well as tissue injuries caused by ionizing radiation. We now demonstrate that the absence of CD47 improves the rate of wound closure for a focal dermal second-degree thermal injury, whereas lack of thrombospondin-1 initially delays wound closure compared to healing in wild type mice. Doppler analysis of the wounded area showed increased blood flow in both CD47 and thrombospondin-1 null mice. Accelerated wound closure in the CD47 null mice was associated with increased fibrosis as demonstrated by a 4-fold increase in collagen fraction. Wound tissue of CD47 null mice showed increased thrombospondin-1 mRNA and protein expression and TGF-ß1 mRNA levels. Activation of latent TGF-ß1 was increased in thermally injured CD47-null tissue as assessed by phosphorylation of the TGF-ß1 receptor-regulated transcription factors SMAD-2 and -3. Overall these results indicate that targeting CD47 may improve the speed of healing thermal injuries, but some level of CD47 expression may be required to limit the long term TGF-ß1-dependent fibrosis of these wounds.