Identification and Classification of Prostate Cancer Identification and Classification Based on Improved Convolution Neural Network.

Prostate cancer is one of the most common cancers in men worldwide, second only to lung cancer. The most common method used in diagnosing prostate cancer is the microscopic observation of stained biopsies by a pathologist and the Gleason score of the tissue microarray images. However, scoring prostate cancer tissue microarrays by pathologists using Gleason mode under many tissue microarray images is time-consuming, susceptible to subjective factors between different observers, and has low reproducibility. We have used the two most common technologies, deep learning, and computer vision, in this research, as the development of deep learning and computer vision has made pathology computer-aided diagnosis systems more objective and repeatable. Furthermore, the U-Net network, which is used in our study, is the most extensively used network in medical image segmentation. Unlike the classifiers used in previous studies, a region segmentation model based on an improved U-Net network is proposed in our research, which fuses deep and shallow layers through densely connected blocks. At the same time, the features of each scale are supervised. As an outcome of the research, the network parameters can be reduced, the computational efficiency can be improved, and the method's effectiveness is verified on a fully annotated dataset.

Supervised Computer-Aided Diagnosis (CAD) Methods for Classifying Alzheimer's Disease-Based Neurodegenerative Disorders.

Alzheimer's disease is incurable at the moment. If it can be appropriately diagnosed, the correct treatment can postpone the patient's illness. To aid in the diagnosis of Alzheimer's disease and to minimize the time and expense associated with manual diagnosis, a machine learning technique is employed, and a transfer learning method based on 3D MRI data is proposed. Machine learning algorithms can dramatically reduce the time and effort required for human treatment of Alzheimer's disease. This approach extracts bottleneck features from the M-Net migration network and then adds a top layer to supervised training to further decrease the dimensionality and delete portions. As a consequence, the transfer network presented in this study has several advantages in terms of computational efficiency and training time savings when used as a machine learning approach for AD-assisted diagnosis. Finally, the properties of all subject slices are combined and trained in the classification layer, completing the categorization of Alzheimer's disease symptoms and standard control. The results show that this strategy has a 1.5 percentage point better classification accuracy than the one that relies exclusively on VGG16 to extract bottleneck features. This strategy could cut the time it takes for the network to learn and improve its ability to classify things. The experiment shows that the method works by using data from OASIS. A typical transfer learning network's classification accuracy is about 8% better with this method than with a typical network, and it takes about 1/60 of the time with this method.

Understanding on CRISPR/Cas9 mediated cutting-edge approaches for cancer therapeutics.

The research focus on CRISPR/Cas9 has gained substantial concentration since the discovery of 'an unusual repeat sequence' reported by Ishino et al. (J Bacteriol 169:5429-5433, 1987) and the journey comprises the recent Nobel Prize award (2020), conferred to Emmanuelle Charpentier and Jennifer Doudna. Cumulatively, the CRISPR has a short, compact, and most discussed success of its application in becoming one of the most versatile and paradigm shifting technologies of Biological Research. Today, the CRISPR/Cas9 genome editing system is almost ubiquitously utilized in many facets of biological research where its tremendous gene manipulation capability has been harnessed to create miracles. From 2012, the CRISPR/Cas 9 system has been showcased in almost 15,000 research articles in the PubMed database, till date. Backed by some strong molecular evidence, the CRISPR system has been utilized in a few clinical trials targeted towards various pathologies. While the area covered by CRISPR is cosmic, this review will focus mostly on the utilization of CRISPR/Cas9 technology in the field of cancer therapy.

Garcinia morella extract confers dopaminergic neuroprotection by mitigating mitochondrial dysfunctions and inflammation in mouse model of Parkinson's disease.

Dopaminergic neuroprotection is the main interest in designing novel therapeutics against Parkinson's disease (PD). In the process of dopaminergic degeneration, mitochondrial dysfunctions and inflammation are significant. While the existing drugs provide symptomatic relief against PD, a therapy conferring total neuroprotection by targeting multiple degenerative pathways is still lacking. Garcinia morella is a common constituent of Ayurvedic medication and has been used for the treatment of inflammatory disorders. The present study investigates whether administration of G. morella fruit extract (GME) in MPTP mouse model of PD protects against dopaminergic neurodegeneration, including the underlying pathophysiologies, and reverses the motor behavioural abnormalities. Administration of GME prevented the loss of dopaminergic cell bodies in the substantia nigra and its terminals in the corpus striatum of PD mice. Subsequently, reversal of parkinsonian behavioural abnormalities, viz. akinesia, catalepsy, and rearing, was observed along with the recovery of striatal dopamine and its metabolites in the experimental model. Furthermore, reduced activity of the mitochondrial complex II in the nigrostriatal pathway of brain of the mice was restored after the administration of GME. Also, MPTP-induced enhanced activation of Glial fibrillary acidic protein (GFAP) and neuronal nitric oxide synthase (nNOS) in the nigrostriatal pathway, which are the markers of inflammatory stress, were found to be ameliorated on GME treatment. Thus, our study presented a novel mode of dopaminergic neuroprotection by G. morella in PD by targeting the mitochondrial dysfunctions and neuroinflammation, which are considered to be intricately associated with the loss of dopaminergic neurons.

Cholesterol contributes to dopamine-neuronal loss in MPTP mouse model of Parkinson's disease: Involvement of mitochondrial dysfunctions and oxidative stress.

Hypercholesterolemia is a known contributor to the pathogenesis of Alzheimer's disease while its role in the occurrence of Parkinson's disease (PD) is only conjecture and far from conclusive. Altered antioxidant homeostasis and mitochondrial functions are the key mechanisms in loss of dopaminergic neurons in the substantia nigra (SN) region of the midbrain in PD. Hypercholesterolemia is reported to cause oxidative stress and mitochondrial dysfunctions in the cortex and hippocampus regions of the brain in rodents. However, the impact of hypercholesterolemia on the midbrain dopaminergic neurons in animal models of PD remains elusive. We tested the hypothesis that hypercholesterolemia in MPTP model of PD would potentiate dopaminergic neuron loss in SN by disrupting mitochondrial functions and antioxidant homeostasis. It is evident from the present study that hypercholesterolemia in naïve animals caused dopamine neuronal loss in SN with subsequent reduction in striatal dopamine levels producing motor impairment. Moreover, in the MPTP model of PD, hypercholesterolemia exacerbated MPTP-induced reduction of striatal dopamine as well as dopaminergic neurons in SN with motor behavioral depreciation. Activity of mitochondrial complexes, mainly complex-I and III, was impaired severely in the nigrostriatal pathway of hypercholesterolemic animals treated with MPTP. Hypercholesterolemia caused oxidative stress in the nigrostriatal pathway with increased generation of hydroxyl radicals and enhanced activity of antioxidant enzymes, which were further aggravated in the hypercholesterolemic mice with Parkinsonism. In conclusion, our findings provide evidence of increased vulnerability of the midbrain dopaminergic neurons in PD with hypercholesterolemia.

Hypercholesterolemia causes psychomotor abnormalities in mice and alterations in cortico-striatal biogenic amine neurotransmitters: Relevance to Parkinson's disease.

The symptoms of Parkinson's disease (PD) include motor behavioral abnormalities, which appear as a result of the extensive loss of the striatal biogenic amine, dopamine. Various endogenous molecules, including cholesterol, have been put forward as putative contributors in the pathogenesis of PD. Earlier reports have provided a strong link between the elevated level of plasma cholesterol (hypercholesterolemia) and onset of PD. However, the role of hypercholesterolemia on brain functions in terms of neurotransmitter metabolism and associated behavioral manifestations remain elusive. We tested in Swiss albino mice whether hypercholesterolemia induced by high-cholesterol diet would affect dopamine and serotonin metabolism in discrete brain regions that would precipitate in psychomotor behavioral manifestations. High-cholesterol diet for 12 weeks caused a significant increase in blood total cholesterol level, which validated the model as hypercholesterolemic. Tests for akinesia, catalepsy, swimming ability and gait pattern (increased stride length) have revealed that hypercholesterolemic mice develop motor behavioral abnormalities, which are similar to the behavioral phenotypes of PD. Moreover, hypercholesterolemia caused depressive-like behavior in mice, as indicated by the increased immobility time in the forced swim test. We found a significant depletion of dopamine in striatum and serotonin in cortex of hypercholesterolemic mice. The significant decrease in tyrosine hydroxylase immunoreactivity in striatum supports the observed depleted level dopamine in striatum, which is relevant to the pathophysiology of PD. In conclusion, hypercholesterolemia-induced depleted levels of cortical and striatal biogenic amines reported hereby are similar to the PD pathology, which might be associated with the observed psychomotor behavioral abnormalities.

L-DOPA treatment in MPTP-mouse model of Parkinson's disease potentiates homocysteine accumulation in substantia nigra.

One of the intermediates of methionine cycle, the homocysteine (Hcy), elevates in plasma of Parkinson's disease (PD) patients undergoing L-DOPA (3,4-dihydroxyphenylalanine) therapy and has been regarded as a risk factor of the disease. Several evidences pointed out that Hcy causes degeneration of dopaminergic neurons. In rodent, elevated level of Hcy in brain or infusion of the same directly into the substantia nigra (SN) potentiates dopaminergic neurodegeneration. However, the influence of L-DOPA therapy on the levels of Hcy in dopamine-rich regions of the brain (striatum and SN) of experimental models of PD is not known. The present study, for the first time, tested the hypothesis that L-DOPA treatment in experimental mouse model of PD potentiates Hcy accumulation in the dopamine-rich regions of the brain. We found a significant elevation of Hcy level in nigrostriatum in naïve as well as parkinsonian mice as a result of chronic L-DOPA treatment. Interestingly, L-DOPA treatment significantly elevates Hcy level in nigra but not in striatum of parkinsonian mice, when compared with L-DOPA naïve group. However, there is no significant decrease in the number of dopaminergic neurons in SN region in the parkinsonian mice given L-DOPA treatment. Thus, the present study demonstrates that L-DOPA treatment potentiates the level of Hcy in the SN without causing aggravated neurodegeneration in parkinsonian mice model.

Cholesterol in Pancreatic ß-Cell Death and Dysfunction: Underlying Mechanisms and Pathological Implications.

The mechanisms or causes of pancreatic ß-cell death as well as impaired insulin secretion, which are the principal events of diabetic etiopathology, are largely unknown. Diabetic complications are known to be associated with abnormal plasma lipid profile, mainly elevated level of cholesterol and free fatty acids. However, in recent years, elevated plasma cholesterol has been implicated as a primary modulator of pancreatic ß-cell functions as well as death. High-cholesterol diet in animal models or excess cholesterol in pancreatic ß-cell causes transporter desensitization and results in morphometric changes in insulin granules. Moreover, cholesterol is also held responsible to cause oxidative stress, mitochondrial dysfunction, and activation of proapoptotic markers leading to ß-cell death. The present review focuses on the pathways and molecularevents that occur in the ß-cell under the influence of excess cholesterol that hampers the basal physiology of the cell leading to the progression of diabetes.

Cholesterol - A putative endogenous contributor towards Parkinson's disease.

Elevated levels of cholesterol and its metabolites (oxysterols) have been reported to be associated not only with several metabolic syndromes, but also become a prognostic risk factor of neurodegenerative diseases particularly Alzheimer's disease. The incidence and the prospect of Alzheimer's disease with respect to elevated levels of cholesterol have been studied extensively and reviewed earlier. Recently, several interesting findings have shown the occurrence of equivalent Parkinsonian pathologies in cellular neuronal models, mediated by oxysterols or excess exposure to cholesterol. In this regard, oxysterols are particular in causing alpha-synuclein aggregation and destruction of dopamine containing neurons in in vitro models, which is linked to their direct influence on oxidative stress provoking potency. Inspite of the significant in vitro reports, which suggest the relativeness of cholesterol or oxysterol towards Parkinsonism, several prospective clinical reports provided a negative or no correlation. However, few prospective clinical studies showed a positive correlation between plasma cholesterol and incidence of Parkinson's disease (PD). Also, few significant studies have convincingly demonstrated that high fat diet exacerbates parkinsonian pathologies, including loss of dopaminergic neurons and oxidative stress parameters in animal models of PD. The present review brings together all the neuropathological proceedings mediated by excess cholesterol or its metabolites in brain in the light of their contribution towards the onset of PD. Also we have reviewed the possibilities of cholesterol lowering efficacy of statin therapy, in reducing the occurrence of PD.

Neuroprotective potential of silymarin against CNS disorders: insight into the pathways and molecular mechanisms of action.

Silymarin, a C25 containing flavonoid from the plant Silybum marianum, has been the gold standard drug to treat liver disorders associated with alcohol consumption, acute and chronic viral hepatitis, and toxin-induced hepatic failures since its discovery in 1960. Apart from the hepatoprotective nature, which is mainly due to its antioxidant and tissue regenerative properties, Silymarin has recently been reported to be a putative neuroprotective agent against many neurologic diseases including Alzheimer's and Parkinson's diseases, and cerebral ischemia. Although the underlying neuroprotective mechanism of Silymarin is believed to be due to its capacity to inhibit oxidative stress in the brain, it also confers additional advantages by influencing pathways such as ß-amyloid aggregation, inflammatory mechanisms, cellular apoptotic machinery, and estrogenic receptor mediation. In this review, we have elucidated the possible neuroprotective effects of Silymarin and the underlying molecular events, and suggested future courses of action for its acceptance as a CNS drug for the treatment of neurodegenerative diseases.