Pseudo-class part prototype networks for interpretable breast cancer classification.

Interpretability in machine learning has become increasingly important as machine learning is being used in more and more applications, including those with high-stakes consequences such as healthcare where Interpretability has been regarded as a key to the successful adoption of machine learning models. However, using confounding/irrelevant information in making predictions by deep learning models, even the interpretable ones, poses critical challenges to their clinical acceptance. That has recently drawn researchers' attention to issues beyond the mere interpretation of deep learning models. In this paper, we first investigate application of an inherently interpretable prototype-based architecture, known as ProtoPNet, for breast cancer classification in digital pathology and highlight its shortcomings in this application. Then, we propose a new method that uses more medically relevant information and makes more accurate and interpretable predictions. Our method leverages the clustering concept and implicitly increases the number of classes in the training dataset. The proposed method learns more relevant prototypes without any pixel-level annotated data. To have a more holistic assessment, in addition to classification accuracy, we define a new metric for assessing the degree of interpretability based on the comments of a group of skilled pathologists. Experimental results on the BreakHis dataset show that the proposed method effectively improves the classification accuracy and interpretability by respectively 8 % and 18 % . Therefore, the proposed method can be seen as a step toward implementing interpretable deep learning models for the detection of breast cancer using histopathology images.

Prognostic Significance of Microvessel Density in Invasive Ductal Carcinoma of Breast.

Background: Breast cancer is the most common malignant tumor and cause of death in women. Factors that play role in tumor metastasis are lymph node involvement, lack of tumor differentiation and hormone receptor expression, high proliferation rate, and angiogenesis. In the present study, we tried to evaluate the microvessel density (MVD) using Immunohistochemistry for the CD34 marker to investigate the amount of angiogenesis in breast cancer and its relationship with other histopathological parameters and compare it with normal tissue. Materials and Methods: 58 paraffin-embedded samples of breast cancer were enrolled. All blocks were sectioned and stained for estrogen receptor (ER), progesterone receptor (PR), human epidermal growth factor 2(HER 2/neu), ki67, and CD34 by immunohistochemistry (IHC) method. Results: The mean age of patients in this study was 49.6 ± 10.6 years. Statistically, there was a significant relationship between the grade of the tumor (P = 0.01), absence of expression of estrogen receptor (P = 0.008), and progesterone receptor (P = 0.003) with MVD. Conclusion: Due to the association between MVD, tumor grade, and absence of ER and PR expression, this valuable marker can play an important role in the prediction of prognosis in breast cancer patients and can lead to new-targeted therapy in the future.

Gastroprotective effect of sumatriptan against indomethacin-, stress- and ethanol-induced gastric damage in male rats: Possible modulatory role of 5-hydroxytryptamine 1B/1D receptors and pro-inflammatory cytokines.

The current study was aimed to investigate the beneficial effect of sumatriptan, a 5-hydroxytryptamine 1B/1D (5HT1B/1D ) receptor agonist, on gastric ulcer in rats via stimulating 5HT1B/1D receptors and suppressing pro-inflammatory cytokines. Rats were allocated into three models of gastric ulcer: indomethacin (30 mg/kg, PO), water immersion restraint stress (WRS) and ethanol (5 ml/kg PO). Animals were administered with sumatriptan (0.01, 0.1, 0.3 and 1 mg/kg, i.p) 30 min before gastric ulcer induction. GR-127935 (0.01 mg/kg, i.p, a selective 5HT1B/1D antagonist) was administered 30 min before sumatriptan (0.1 mg/kg) injection. Macroscopic assessments (J-score), ELISA analysis of tumour necrosis factor-alpha (TNF-α) and interleukin-1beta (IL-1ß) and histopathological changes were performed on the rat's stomach tissues. Gastric ulcer induction in three models caused an increase in J-score, TNF-α, IL-1ß and microscopic features. Sumatriptan (0.1 mg/kg) significantly improved gastric injury induced by indomethacin, WRS and ethanol through the reduction in the J-score, TNF-α, IL-1ß and microscopic lesions. Concurrent administration of GR-127935 (0.01 mg/kg) with sumatriptan (0.1 mg/kg) reversed the gastroprotective effect of sumatriptan in three models. Sumatriptan possessed gastroprotective effects on indomethacin-, WRS- and ethanol-induced gastric damage in rats via the possible involvement of the 5HT1B/1D receptors.

Cardiac Mass and Cerebrovascular Accident as Primary Manifestations of Churg-Strauss Syndrome.

Churg-Strauss syndrome (CSS), recently named eosinophilic granulomatosis with polyangiitis (EGPA), is a rare form of systemic vasculitis with extravascular granulomas occurring in patients with asthma and tissue eosinophilia. We represent a large left ventricular granuloma, confirmed by histopathologic evaluation, detected as a ventricular mass by echocardiography in a 45-year-old asthmatic male who was admitted for a cerebrovascular accident. Paraclinical and histopathologic findings confirmed the diagnosis of EGPA. As cardiac involvement in patients with EGPA is associated with poor prognosis, routine echocardiographic evaluation of these patients is suggested.

Single Nucleotide Polymorphisms (SNP) and SNP-SNP Interactions of the Surfactant Protein Genes Are Associated With Idiopathic Pulmonary Fibrosis in a Mexican Study Group; Comparison With Hypersensitivity Pneumonitis.

Surfactant proteins (SPs) are important for normal lung function and innate immunity of the lungs and their genes have been identified with significant genetic variability. Changes in quantity or quality of SPs due to genetic mutations or natural genetic variability may alter their functions and contribute to the host susceptibility for particular diseases. Alternatively, SP single nucleotide polymorphisms (SNPs) can serve as markers to identify disease risk or response to therapies, as shown for other genes in a number of other studies. In the current study, we evaluated associations of SFTP SNPs with idiopathic pulmonary fibrosis (IPF) by studying novel computational models where the epistatic effects (dominant, additive, recessive) of SNP-SNP interactions could be evaluated, and then compared the results with a previously published hypersensitivity pneumonitis (HP) study where the same novel models were used. Mexican Hispanic patients (IPF=84 & HP=75) and 194 healthy control individuals were evaluated. The goal was to identify SP SNPs and SNP-SNP interactions that associate with IPF as well as SNPs and interactions that may be unique to each of these interstitial diseases or common between them. We observed: 1) in terms of IPF, i) three single SFTPA1 SNPs to associate with decreased IPF risk, ii) three SFTPA1 haplotypes to associate with increased IPF risk, and iii) a number of three-SNP interactions to associate with IPF susceptibility. 2) Comparison of IPF and HP, i) three SFTPA1 and one SFTPB SNP associated with decreased risk in IPF but increased risk in HP, and one SFTPA1 SNP associated with decreased risk in both IPF and HP, ii) a number of three-SNP interactions with the same or different effect pattern associated with IPF and/or HP susceptibility, iii) one of the three-SNP interactions that involved SNPs of SFTPA1, SFTPA2, and SFTPD, with the same effect pattern, was associated with a disease-specific outcome, a decreased and increased risk in HP and IPF, respectively. This is the first study that compares the SP gene variants in these two phenotypically similar diseases. Our findings indicate that SNPs of all SFTPs may play an important role in the genetic susceptibility to IPF and HP. Importantly, IPF and HP share some SP genetic variants, suggesting common pathophysiological mechanisms and pathways regarding surfactant biogenesis, but also some differences, highlighting the diverse underlying pathogenic mechanisms between an inflammatory-driven fibrosis (HP) and an epithelial-driven fibrosis (IPF). Alternatively, the significant SNPs identified here, along with SNPs of other genes, could serve as markers to distinguish these two devastating diseases.

All-Trans Retinoic Acid (atRA) effectively improves liver steatosis in a rabbit model of high fat induced liver steatosis.

The aim of this study is to evaluate the role of All-Trans Retinoic Acid, the biologically active metabolite of retinoids, on liver steatosis in a rabbit model of high fat induced lever steatosis. 30 male rabbits were evaluated in 5 groups: group 1 treated with normal diet, group 2-5 included rabbit's groups 2 to 5 were fed on high cholesterol diet, group 2 received no drugs, group 3 received atorvastatin, group 4 received atRA, and group 5 received both the drugs. the liver was obtained for histopathological evaluation. oral administration of atRA, atorvastatin or their combination significantly decreased serum levels of total cholesterol, LDL, AST and ALT. atorvastatin slightly but atRA remarkably decreased liver steatosis where the difference was significant. atRA group showed the highest TAC and the lowest PCO concentrations. atRA can be effective in reducing liver steatosis and its antioxidant effect plays a crucial role in the process.HighlightsNon-alcoholic fatty liver disease (NAFLD) is the most common disorder of the liver in general population and is strongly associated with metabolic risk factors including hyperlipidaemia, obesity and diabetes.atRA is very effective in reducing liver steatosis and its antioxidant effect plays a crucial role in the process.we suggest focussing on other aspects of liver steatosis such as carbohydrate metabolism and insulin resistance in order to find better ways of controlling and treating liver steatosis.

High grade breast ductal carcinomas have high density of tumor-associated macrophages.

BACKGROUND: The role of tumor-associated macrophages (TAMs) is double-natured and still controversial. Depending on different settings, macrophages may suppress or promote tumor growth. TAM density may be one of the predictive factors of treatment outcome in cancer patients. AIM: To evaluate the density of tumor-associated macrophages in breast cancer and its relationship with various histopathologic findings. MATERIALS AND METHODS: 55 patients with invasive ductal carcinoma of breast who underwent mastectomy were enrolled. Sections of tumor samples were stained and the density of CD68+ cells was evaluated. RESULTS: There was an association between estrogen receptor (ER) expression and CD68 density (p = 0.010) as the higher densities of CD68 were seen in ER negative tumors. Moreover, there was a significant relationship between histological grade and CD68 density (p = 0.006). CONCLUSION: The higher TAM density is associated with higher tumor grade and negative ER expression in breast cancer tissues. These findings revealed that inflammation could have an important role in malignancies.

Can Prophylactic High Flow of Humidified and Warmed Filtered Air Improve Survival from Bacterial Pneumonia and SARS-CoV-2 in Elderly Individuals? The Role of Surfactant Protein A.

In this opinion article, we discuss a serendipitous observation we made in a study investigating survival in aged mice after bacterial infection. This observation involved a non-invasive ventilation approach that led to variable and higher survival in male and female mice with different genetic backgrounds for the innate immune molecule, surfactant protein A (SP-A). We suggest that employing the best ventilatory modality, whether that be HFNC or another method, may augment the role of other factors such as SP-A genetics and sex in a personalized approach, and may ultimately improve the outcome.

Investigation of the Molecular Mechanism of Coagulopathy in Severe and Critical Patients With COVID-19.

Coagulopathy is a frequently reported finding in the pathology of coronavirus disease 2019 (COVID-19); however, the molecular mechanism, the involved coagulation factors, and the role of regulatory proteins in homeostasis are not fully investigated. We explored the dynamic changes of nine coagulation tests in patients and controls to propose a molecular mechanism for COVID-19-associated coagulopathy. Coagulation tests including prothrombin time (PT), partial thromboplastin time (PTT), fibrinogen (FIB), lupus anticoagulant (LAC), proteins C and S, antithrombin III (ATIII), D-dimer, and fibrin degradation products (FDPs) were performed on plasma collected from 105 individuals (35 critical patients, 35 severe patients, and 35 healthy controls). There was a statically significant difference when the results of the critical (CRT) and/or severe (SVR) group for the following tests were compared to the control (CRL) group: PTCRT (15.014) and PTSVR (13.846) (PTCRL = 13.383, p < 0.001), PTTCRT (42.923) and PTTSVR (37.8) (PTTCRL = 36.494, p < 0.001), LACCRT (49.414) and LACSVR (47.046) (LACCRL = 40.763, p < 0.001), FIBCRT (537.66) and FIBSVR (480.29) (FIBCRL = 283.57, p < 0.001), ProCCRT (85.57%) and ProCSVR (99.34%) (ProCCRL = 94.31%, p = 0.04), ProSCRT (62.91%) and ProSSVR (65.06%) (ProSCRL = 75.03%, p < 0.001), D-dimer (p < 0.0001, χ2 = 34.812), and FDP (p < 0.002, χ2 = 15.205). No significant association was found in the ATIII results in groups (ATIIICRT = 95.71% and ATIIISVR = 99.63%; ATIIICRL = 98.74%, p = 0.321). D-dimer, FIB, PT, PTT, LAC, protein S, FDP, and protein C (ordered according to p-values) have significance in the prognosis of patients. Disruptions in homeostasis in protein C (and S), VIII/VIIIa and V/Va axes, probably play a role in COVID-19-associated coagulopathy.

Protective effect of modafinil on skin flap survival in the experimental random-pattern skin flap model in rats: The role of ATP-sensitive potassium channels and nitric oxide pathway.

BACKGROUND: The brain-stimulating agent modafinil acts through nitric oxide (NO) and adenosine triphosphate (ATP)-sensitive potassium (KATP) channels, involved in the skin flap survival (SFS). The main aim of this study was to investigate the efficacy of modafinil on SFS in rats through the involvement of NO pathway and KATP channels. METHODS: Using controlled experiment study design, we enrolled a sample of Wistar male rats. Different doses of modafinil (10, 25, 50, and 100 mg/kg) were injected intraperitoneally (i.p.) before the surgery. L-NAME (non-selective nitric oxide synthase [NOS] inhibitor), aminoguanidine (inducible NOS inhibitor), and 7-nitroindazole (neuronal NOS inhibitor) were administered prior to modafinil. The role of KATP channels was determined by coadministering glibenclamide (KATP channel blocker) or cromakalim (KATP channel opener) with modafinil. The predictor variables were administration of different doses of modafinil, and the coadministration of modafinil with L-NAME, aminoguanidine, 7-nitroindazole, glibenclamide, and cromakalim. The main outcome variables included the percentage of necrotic area (PNA) in flap tissues, histopathological results, vascular endothelial growth factor (VEGF) immunohistochemical (IHC) staining, and nitrite concentrations. Appropriate statistics were computed considering p-value ≤ 0.05 significant. RESULTS: Modafinil 25 mg/kg was the most effective dose (PNA: 26 [95% CI: 19-33]) vs. control (PNA: 81 [95% CI: 71-92]) (p< 0.001). All NOS inhibitors significantly reversed the protective effect of modafinil (p< 0.001). Non-effective dose of cromakalim had a synergistic effect with the sub-effective dose of modafinil (10 mg/kg), while glibenclamide reversed the effect of modafinil 25 mg/kg (p< 0.001). CONCLUSIONS: Modafinil increases SFS mediated by NO pathway and KATP channels, which could therefore be a target to improve SFS.

Sumatriptan reduces severity of status epilepticus induced by lithium-pilocarpine through nitrergic transmission and 5-HT1B/D receptors in rats: A pharmacological-based evidence.

Status epilepticus (SE) is a life-threatening neurologic disorder that can be as both cause and consequence of neuroinflammation. In addition to previous reports on anti-inflammatory property of the anti-migraine medication sumatriptan, we have recently shown its anticonvulsive effects on pentylenetetrazole-induced seizure in mice. In the present study, we investigated further (i) the effects of sumatriptan in the lithium-pilocarpine SE model in rats, and (ii) the possible involvement of nitric oxide (NO), 5-hydroxytryptamin 1B/1D (5-HT1B/1D ) receptor, and inflammatory pathways in such effects of sumatriptan. Status epilepticus was induced by lithium chloride (127 mg/kg, i.p) and pilocarpine (60 mg/kg, i.p.) in Wistar rats. While SE induction increased SE scores and mortality rate, sumatriptan (0.001-1 mg/kg, i.p.) improved it (P < 0.001). Administration of the selective 5-HT1B/1D antagonist GR-127935 (0.01 mg/kg, i.p.) reversed the anticonvulsive effects of sumatriptan (0.01 mg/kg, i.p.). Although both tumor necrosis factor-α (TNF-α) and NO levels were markedly elevated in the rats' brain tissues post-SE induction, pre-treatment with sumatriptan significantly reduced both TNF-α (P < 0.05) and NO (P < 0.001) levels. Combined GR-127935 and sumatriptan treatment inhibited these anti-inflammatory effects of sumatriptan, whereas combined non-specific NOS (L-NAME) or selective neuronal NOS (7-nitroindazole) inhibitors and sumatriptan further reduced NO levels. In conclusion, sumatriptan exerted a protective effect against the clinical manifestations and mortality rate of SE in rats which is possibly through targeting 5-HT1B/1D receptors, neuroinflammation, and nitrergic transmission.

Protective effect of dapsone against renal ischemia-reperfusion injury in rat.

Background: Ischemia/reperfusion can cause injury to tissues and compromise functionality of organs due to inflammatory processes. Significantly, development of these effects in kidney tissue has been a challenging issue that leads to acute renal injury. In this study, anti-inflammatory, anti-oxidative, and protective features of dapsone on kidney ischemia/reperfusion injury were investigated.Material and methods: Renal ischemia was induced in rats by bilateral renal arteries clamping for 45 min followed by 24 h reperfusion phase. The effects of different doses of dapsone (1, 3, 10 mg/kg) on ischemia/reperfusion injury in kidney tissue were investigated by targeting BUN, Creatinine, LDH, MDA, MPO, IL-1ß, TNF-α, and NFκB. In addition histopathological examination was performed by H&E staining method.Results and discussion: Comparing the findings of this study showed significant reduction in BUN and LDH in 10 mg/kg dapsone received groups, and Cr, MDA, and MPO in 3 mg/kg dapsone received groups. The serum level of TNF-α was significantly decreased with both doses of 3 and 10 mg/kg dapsone. The same results were observed in the serum level of IL-1ß and NFκB. Besides, remarkable improvement in histological damages was also observed with dapsone treatment.Conclusion: These results support the hypothesis that the positive effects of dapsone on the renal ischemia/reperfusion injury are mediated by modulating inflammatory cascades.

High GD2 expression defines breast cancer cells with enhanced invasiveness.

INTRODUCTION: Breast cancer is the most frequently diagnosed cancer among women. Cancer stem cells (CSCs) are suggested to be responsible for tumor initiation, progression, metastasis, recurrence and drug resistance. This study was conducted to evaluate the clinical significance of GD2, a newly suggested CSC marker and two other traditional CSC markers, CD44 and CD24 in breast cancer patients. MATERIAL AND METHODS: A total of 168 primary breast cancer tissues were evaluated in terms of GD2, CD44 and CD24 expression using tissue microarray. Then, the correlation of expression levels of these markers with patients' clinicopathological characteristics was assessed. RESULTS: Higher GD2 expression was mainly found in patients with advanced histological grade (p = 0.02), presence of lymph node invasion (p = 0.04), larger size of tumors (p = 0.04) and older age (p = 0.04). Breast cancer samples with advanced histological grade also showed higher CD44 (p = 0.03) and CD24 expression (p = 0.05). A significant positive association was found between increased CD24 expression and lymph node involvement (p = 0.01). Furthermore, GD2-high/CD44-high/CD24-low phenotype was frequently seen in breast cancer samples with positive lymph node involvement (p = 0.05). CONCLUSION: In summary, increased expression of GD2 may define more aggressive tumor behavior in breast cancer. GD2 can well be considered as a diagnostic and prognostic marker in breast cancer.

Fascin overexpression is associated with higher grades of breast cancer.

In the present study, we tried to evaluate the relationship between Fascin molecule expression and other histopathologic parameters, especially tumor grade and hormone profile. Sixty-one malignant breast tumors were enrolled in this study. Fascin marker staining was performed on paraffin blocks of breast samples using immunohistochemistry (IHC) method. The age range of patients was 26-87 years, with an average of 48.41 ±1.68. Our results showed that fascin expression was significantly higher in tumors with high grade histology, lymph node involvement and larger tumor size (p = 0.04, 0.04, 0.04, respectively). Also fascin expression in triple negative tumors was significantly higher than other molecular subtypes (p = 0.001). fascin can be used as an important marker in evaluating breast cancer especially in triple negative tumors.

Giant Cell Tumor of the Capitate Bone.

This case report describes a 16-year-old female patient with a giant cell tumor in her right capitate bone. The tumor was removed by intralesional curettage. A high-speed burr was used to extend the margins of the curettage, and alcohol irrigation was used for adjuvant therapy. The cavity of the capitate was filled with allogenic bone graft. There was no recurrence after 2 years of follow-up, and the right wrist radiographs demonstrated healing of the lesion.

Relationship between interstitial CD34 positive cells and active phase of lupus nephritis.

OBJECTIVE: Lupus nephritis is one of the most serious and common complications of systemic lupus erythematosus. It has an unpredictable course, and the type, severity, and activity of renal lesions cannot be assessed only by clinical and laboratory findings. The aim of the present study was to determine the relationship between the expression of CD34 and the histopathological findings of lupus nephritis. METHODS: A total of 73 renal biopsy samples of patients with a diagnosis of lupus nephritis were examined for CD34 expression by immunohistochemistry. Samples without staining were considered as 0, mild staining as 1+, moderate as 2+, and strong staining as 3+. The relationship between CD34 expression and histopathological and clinical data (including activity index, chronicity index, lupus nephritis class, age, sex, blood pressure, complete blood count, renal function tests, and serological findings) was analyzed. RESULTS: The mean age of the patients was 29.3±11.3 years. CD34 was expressed in all of the cases but with different intensities. There was a significant relationship between the expression of CD34 and the activity index, as a strong expression was seen in lower activity indices (p<0.001). CD34 expression was correlated with patients' white blood cell (WBC) count and systolic blood pressure (SBP). Patients with strong (score 3) CD34 expression had higher SBPs and lower WBC counts (p=0.03 and 0.04, respectively). CONCLUSION: A strong interstitial expression of CD34 was observed in lower activity indices. It seems that CD34 expression could play a protective role in lupus nephritis and could reduce renal activity.

All-trans retinoic acid effectively reduces atheroma plaque size in a rabbit model of high-fat-induced atherosclerosis.

BACKGROUND: Atherosclerosis (AS) is one of the most prevalent causes of death around the world. Since there are different types of risk factors, different types of medications focus on preventing atheromas and plaques from establishing or on preventing established plaques from growing. OBJECTIVES: The aim of this study was to evaluate the effect of all-trans retinoic acid (atRA) on AS in a rabbit model of fat-induced AS. MATERIAL AND METHODS: Atherosclerosis was induced by a high-fat diet (HFD) for 75 days. Thirty rabbits were randomly divided into 5 groups. Group 1 was the negative control group and received a normal diet. The animals in the other groups were fed a HFD. Group 2 (the AS positive control group) received no drugs, Group 3 received atorvastatin orally (20 mg/kg/day), Group 4 received atRA (5 mg/kg/day, orally), and Group 5 received both drugs. All medications were started on day 45 and continued until the end of the study. Fasting blood samples were obtained for lipid profile evaluation. The aorta sections were evaluated for maximum wall and intima thickness. RESULTS: Oral administration of atRA, atorvastatin or their combination significantly improved serum lipid profile (p < 0.001). Atorvastatin and atRA significantly decreased serum total cholesterol and LDL-cholesterol levels in HFD (p < 0.001). No difference was found in serum HDL-cholesterol levels among the studied groups. The HFD group (Group 2 - positive control) showed significant intima irregularities with fat deposition and foamy macrophage accumulation (atheroma). Administration of atRA and atorvastatin significantly decreased the size of atherosclerotic plaques (intima thickness). The maximum vessel wall and intima thickness were significantly decreased after atRA and atorvastatin administration (p < 0.001). No difference was found between atRA and atorvastatin effectiveness, but combination therapy significantly decreased AS size in comparison to using either of the drugs alone (p < 0.001). CONCLUSIONS: In reducing AS plaque size, atRA is as effective as atorvastatin. Additionally, the combination therapy of atRA and atorvastatin decreased AS size much more effectively, showing their synergistic effect. atRA can also improve the serum lipid profile.