An Intelligent Diabetic Patient Tracking System Based on Machine Learning for E-Health Applications.

BACKGROUND: Continuous surveillance helps people with diabetes live better lives. A wide range of technologies, including the Internet of Things (IoT), modern communications, and artificial intelligence (AI), can assist in lowering the expense of health services. Due to numerous communication systems, it is now possible to provide customized and distant healthcare. MAIN PROBLEM: Healthcare data grows daily, making storage and processing challenging. We provide intelligent healthcare structures for smart e-health apps to solve the aforesaid problem. The 5G network must offer advanced healthcare services to meet important requirements like large bandwidth and excellent energy efficacy. METHODOLOGY: This research suggested an intelligent system for diabetic patient tracking based on machine learning (ML). The architectural components comprised smartphones, sensors, and smart devices, to gather body dimensions. Then, the preprocessed data is normalized using the normalization procedure. To extract features, we use linear discriminant analysis (LDA). To establish a diagnosis, the intelligent system conducted data classification utilizing the suggested advanced-spatial-vector-based Random Forest (ASV-RF) in conjunction with particle swarm optimization (PSO). RESULTS: Compared to other techniques, the simulation's outcomes demonstrate that the suggested approach offers greater accuracy.

Alpha-Synuclein Targeting Therapeutics for Parkinson's Disease and Related Synucleinopathies.

α-Synuclein (asyn) is a key pathogenetic factor in a group of neurodegenerative diseases generically known as synucleinopathies, including Parkinson's disease (PD), dementia with Lewy bodies (DLB) and multiple system atrophy (MSA). Although the initial triggers of pathology and progression are unclear, multiple lines of evidence support therapeutic targeting of asyn in order to limit its prion-like misfolding. Here, we review recent pre-clinical and clinical work that offers promising treatment strategies to sequester, degrade, or silence asyn expression as a means to reduce the levels of seed or substrate. These diverse approaches include removal of aggregated asyn with passive or active immunization or by expression of vectorized antibodies, modulating kinetics of misfolding with small molecule anti-aggregants, lowering asyn gene expression by antisense oligonucleotides or inhibitory RNA, and pharmacological activation of asyn degradation pathways. We also discuss recent technological advances in combining low intensity focused ultrasound with intravenous microbubbles to transiently increase blood-brain barrier permeability for improved brain delivery and target engagement of these large molecule anti-asyn biologics.

Viral alpha-synuclein knockdown prevents spreading synucleinopathy.

The accumulation of aggregated alpha-synuclein (α-syn) in Parkinson's disease, dementia with Lewy bodies and multiple system atrophy is thought to involve a common prion-like mechanism, whereby misfolded α-syn provides a conformational template for further accumulation of pathological α-syn. We tested whether silencing α-syn gene expression could reduce native non-aggregated α-syn substrate and thereby disrupt the propagation of pathological α-syn initiated by seeding with synucleinopathy-affected mouse brain homogenates. Unilateral intracerebral injections of adeno-associated virus serotype-1 encoding microRNA targeting the α-syn gene reduced the extent and severity of both the α-syn pathology and motor deficits. Importantly, a moderate 50% reduction in α-syn was sufficient to prevent the spread of α-syn pathology to distal brain regions. Our study combines behavioural, immunohistochemical and biochemical data that strongly support α-syn knockdown gene therapy for synucleinopathies.

α-Synuclein strains target distinct brain regions and cell types.

The clinical and pathological differences between synucleinopathies such as Parkinson's disease and multiple system atrophy have been postulated to stem from unique strains of α-synuclein aggregates, akin to what occurs in prion diseases. Here we demonstrate that inoculation of transgenic mice with different strains of recombinant or brain-derived α-synuclein aggregates produces clinically and pathologically distinct diseases. Strain-specific differences were observed in the signs of neurological illness, time to disease onset, morphology of cerebral α-synuclein deposits and the conformational properties of the induced aggregates. Moreover, different strains targeted distinct cellular populations and cell types within the brain, recapitulating the selective targeting observed among human synucleinopathies. Strain-specific clinical, pathological and biochemical differences were faithfully maintained after serial passaging, which implies that α-synuclein propagates via prion-like conformational templating. Thus, pathogenic α-synuclein exhibits key hallmarks of prion strains, which provides evidence that disease heterogeneity among the synucleinopathies is caused by distinct α-synuclein strains.

Outcome of radial scar/complex sclerosing lesion associated with epithelial proliferations with atypia diagnosed on breast core biopsy: results from a multicentric UK-based study.

AIMS: The clinical significance of radial scar (RS)/complex sclerosing lesion (CSL) with high-risk lesions (epithelial atypia) diagnosed on needle core biopsy is not well defined. We aimed at assessing the upgrade rate to ductal carcinoma in situ (DCIS) and invasive carcinoma on the surgical excision specimen in a large cohort with RS/CSL associated with atypia. METHODS: 157 women with a needle core biopsy diagnosis of a RS/CSL with atypia and follow-up histology were studied. Histological findings, including different forms of the atypical lesions and final histological outcome in the excision specimens, were retrieved and analysed, and the upgrade rates for malignancy and for invasive carcinoma were calculated. RESULTS: 69.43% of the cases were associated with atypical ductal hyperplasia (ADH) or atypia not otherwise classifiable, whereas lobular neoplasia was seen in 21.66%. On final histology, 39 cases were malignant (overall upgrade rate of 24.84%); 12 were invasive and 27 had DCIS. The upgrade differed according to the type of atypia and was highest for ADH (35%). When associated with lobular neoplasia, the upgrade rate was 11.76%. The upgrade rate's variability was also considerably lower when considering the upgrade to invasive carcinoma alone for any associated lesion. CONCLUSIONS: The upgrade rate for ADH diagnosed on needle core biopsy with RS is similar to that of ADH without RS and therefore should be managed similarly. RS associated with lobular neoplasia is less frequently associated with malignant outcome. Most lesions exhibiting some degree of atypia showed a similar upgrade rate to invasive carcinoma. Management of RS should be based on the concurrent atypical lesion.

Correction: Population Distribution Analyses Reveal a Hierarchy of Molecular Players Underlying Parallel Endocytic Pathways.

[This corrects the article DOI: 10.1371/journal.pone.0100554.].

The loss of the kinases SadA and SadB results in early neuronal apoptosis and a reduced number of progenitors.

The neurons that form the mammalian neocortex originate from progenitor cells in the ventricular (VZ) and subventricular zone (SVZ). Newborn neurons are multipolar but become bipolar during their migration from the germinal layers to the cortical plate (CP) by forming a leading process and an axon that extends in the intermediate zone (IZ). Once they settle in the CP, neurons assume a highly polarized morphology with a single axon and multiple dendrites. The AMPK-related kinases SadA and SadB are intrinsic factors that are essential for axon formation during neuronal development downstream of Lkb1. The knockout of both genes encoding Sad kinases (Sada and Sadb) results not only in a loss of axons but also a decrease in the size of the cortical plate. The defect in axon formation has been linked to a function of Sad kinases in the regulation of microtubule binding proteins. However, the causes for the reduced size of the cortical plate in the Sada-/-;Sadb-/- knockout remain to be analyzed in detail. Here we show that neuronal cell death is increased and the number of neural progenitors is decreased in the Sada-/-;Sadb-/- CP. The reduced number of progenitors is a non-cell autonomous defect since they do not express Sad kinases. These defects are restricted to the neocortex while the hippocampus remains unaffected.

Dysplasia in Barrett's oesophagus: p53 immunostaining is more reproducible than haematoxylin and eosin diagnosis and improves overall reliability, while grading is poorly reproducible.

AIMS: p53 immunostaining in Barrett's oesophagus (BO) has been shown to be predictive of progression, but data regarding its generalizability to routine practice are lacking. This study compared the reliability of p53 and dysplasia interpretation and grading. METHODS AND RESULTS: Seventy-two cases encompassing the full spectrum of BO were circulated to 10 pathologists from four institutions after a brief training session in p53 interpretation. Each pathologist classified cases on haematoxylin and eosin (H&E) alone using the Vienna classification and assessed the p53 staining using a qualitative system. Agreement was assessed using kappa statistics. For the four-tier Vienna system, the average unweighted kappa was 0.30. Weighted kappa values varied from 0.27 to 0.69 with an average of 0.47. When grouped into definite dysplasia versus no definite dysplasia the average kappa was 0.55, but the kappa for low-grade dysplasia (LGD) versus high-grade dysplasia (HGD) was only 0.31. For p53, using the three recognized patterns, the unweighted kappa was 0.6 (confidence interval 0.58-0.63). When cases were evaluated with both H&E and p53 the average kappa was 0.61 for definite dysplasia versus the rest. CONCLUSIONS: p53 immunohistochemistry interpretation is more reliable than dysplasia diagnosis, even with limited training. As it is predictive of prognosis and improves diagnostic reproducibility, it is suitable for routine use by pathologists as an adjunct to dysplasia diagnosis. The distinction of LGD versus HGD was poor. This study supports simplifying dysplasia diagnosis into 'present', 'indefinite' or 'absent', and the use of p53 as an ancillary marker in difficult cases. This should help to prevent overdiagnosis of dysplasia and inappropriate treatment.

Development of Nonviral Vectors Targeting the Brain as a Therapeutic Approach For Parkinson's Disease and Other Brain Disorders.

Parkinson's disease (PD) is a debilitating neurodegenerative disease characterized by tremor, rigidity, bradykinesia, and postural instability, for which there is no effective treatment available till date. Here, we report the development of nonviral vectors specific for neuronal cells that can deliver short interfering RNA (siRNA) against the α-synuclein gene (SNCA), and prevent PD-like symptoms both in vitro and in vivo. These vectors not only help siRNA duplexes cross the blood-brain barrier in mice, but also stabilize these siRNAs leading to a sustainable 60-90% knockdown of α-synuclein protein. Mice treated with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine rapidly develop PD-like symptoms which were significantly alleviated when SNCA was knocked down using our vectors. Together, our data not only confirm the central role of α-synuclein in the onset of PD, but also provide a proof of principle that these nonviral vectors can be used as novel tools to design effective strategies to combat central nervous system diseases.

Reduction-sensitive amphiphilic triblock copolymers self-assemble into stimuli-responsive micelles for drug delivery.

Polymeric nanostructures obtained through self-assembly of reduction-sensitive amphiphilic triblock copolymers were investigated as potential drug delivery systems. The characteristic feature of these polymers is their cleavable disulfide bond in the center of the hydrophobic block. Therefore, the triblock copolymers can be cleaved into amphiphilic diblock copolymers. A poly(2-hydroxyethyl methacrylate)-b-poly(butyl methacrylate)-S-S-poly(butyl methacrylate)-b-poly(2-hydroxyethyl methacrylate) (PHEMA-b-(PBMA-S-S-PBMA)-b-PHEMA) triblock copolymer was synthesized. It self-assembled into micelles which were used to encapsulate hydrophobic dye molecules (Nile Red, BodiPy 630/650) as model payloads. The self-assembled nanostructures disintegrated upon reduction of the disulfide bond, releasing their cargo and yielding larger particles that formed aggregates in solution after 24 h. A burst release of payload was shown within the first 15 min, followed by a constant release over several hours. As concentration gradients of reducing agents are commonly found in biological systems, the micelles could be used as redox-sensitive nanocarriers for the intracellular delivery of drugs.

Ginsenoside Rb1 inhibits fibrillation and toxicity of alpha-synuclein and disaggregates preformed fibrils.

Compelling evidence indicates that α-synuclein (α-syn) aggregation plays a central role in the pathogenesis of Parkinson's disease (PD) and other synucleinopathies. Identification of compounds that inhibit or reverse the aggregation process may thus represent a viable therapeutic strategy against PD and related disorders. Ginseng is a well-known medicinal plant that has been used in East Asia for more than two thousand years to treat several conditions. It is now understood that the pharmacological properties of ginseng can be attributed to its biologically active components, the ginsenosides, which in turn have been shown to have neuroprotective properties. We therefore sought to determine for the first time, the potential of the most frequently used and studied ginsenosides, namely Rg1, Rg3 and Rb1, as anti-amyloidogenic agents. The effect of Rg1, Rg3 and Rb1 on α-syn aggregation and toxicity was determined by an array of biophysical, biochemical and cell-culture-based techniques. Among the screened ginsenosides, only Rb1 was shown to be a potent inhibitor of α-syn fibrillation and toxicity. Additionally, Rb1 exhibited a strong ability to disaggregate preformed fibrils and to inhibit the seeded polymerization of α-syn. Interestingly, Rb1 was found to stabilize soluble non-toxic oligomers with no ß-sheet content, that were susceptible to proteinase K digestion, and the binding of Rb1 to those oligomers may represent a potential mechanism of action. Thus, Rb1 could represent the starting point for designing new molecules that could be utilized as drugs for the treatment of PD and related disorders.

Population distribution analyses reveal a hierarchy of molecular players underlying parallel endocytic pathways.

Single-cell-resolved measurements reveal heterogeneous distributions of clathrin-dependent (CD) and -independent (CLIC/GEEC: CG) endocytic activity in Drosophila cell populations. dsRNA-mediated knockdown of core versus peripheral endocytic machinery induces strong changes in the mean, or subtle changes in the shapes of these distributions, respectively. By quantifying these subtle shape changes for 27 single-cell features which report on endocytic activity and cell morphology, we organize 1072 Drosophila genes into a tree-like hierarchy. We find that tree nodes contain gene sets enriched in functional classes and protein complexes, providing a portrait of core and peripheral control of CD and CG endocytosis. For 470 genes we obtain additional features from separate assays and classify them into early- or late-acting genes of the endocytic pathways. Detailed analyses of specific genes at intermediate levels of the tree suggest that Vacuolar ATPase and lysosomal genes involved in vacuolar biogenesis play an evolutionarily conserved role in CG endocytosis.

Prognostic significance of lymphatic invasion in lymph node-positive breast carcinoma: findings from a large case series with long-term follow-up using immunohistochemical endothelial marker.

The poor prognostic significance of lymphatic invasion (LI) in breast carcinoma (BC) as a whole and in lymph node (LN)-negative patients in particular has been recognized in several studies; however, its prognostic role in LN-positive patients is still questionable. Aim of the current study was to assess prognostic role of LI in LN-positive BC specimens. Sections from non-selected 557 LN-positive BC specimens were stained with antibody to podoplanin/D2-40. LI was identified and correlated with clinicopathological features and patients' outcome. Twenty-year overall survival (OS), disease-free interval (DFI), and development of distant metastasis (DM) or recurrence were known for all patients. LI was detected in 262/557 (47%) of specimens ranging from 1 to 350 lesion per tumor section. Its presence was associated with higher grade tumors (P<0.0001), negative hormonal receptors (P<0.0001), high HER-2 expression (P=0.006), and with increased number of positive LNs (P=0.019). In the whole LN-positive BC, presence of LI was a poor prognostic factor for OS, DFI, and development of DM both in univariate and in multivariate analysis. In further stratification of patients, LI was associated with poorer prognosis in patients with single positive LN and not in patients with >1 positive LN. In T1N1 stage, LI was highly associated with poor OS (P=0.002), DFI (P<0.0001), and DM (P<0.0001). In T2N1 patients, LI was associated only with poorer DFI (P=0.037) but not with death or DM. In the two former patient groups, LI lost significance in multivariate analysis. In conclusion, LI is a poor prognostic factor in LN-positive BC particularly for patients having single positive LN. LI therefore would add further prognostic significance when considered in treatment in those patients. We recommend incorporation of LI in breast carcinoma staging and in prognostic indices.

Outcome of pure mucocele-like lesions diagnosed on breast core biopsy.

AIM: Current guidelines recommend that mucocele-like lesions (MLL) of the breast diagnosed on needle core biopsy (NCB) should be categorized as a lesion of uncertain malignant potential (B3). However, data on the outcome of MLL diagnosed on NCB remains limited due to the rarity of this lesion. The aim of this study was to assess the outcome of pure MLL without atypia diagnosed on NCB using a large series of cases and a review of the literature to provide evidence that can guide management. METHODS AND RESULTS: Patients who underwent diagnostic excision biopsy after a core biopsy diagnosis of MLL without atypia were identified from several centres. Two of 54 patients (4%) with MLL without atypia on core biopsy had ductal carcinoma in situ in the subsequent excision specimen. This is similar to the rate in previous studies of 4% (four of 106). If there is atypia in the core biopsy, previous studies found that the frequency of malignancy is much higher at 21% (seven of 33). CONCLUSIONS: Our results provide evidence that pure MLL without atypia diagnosed on NCB is usually associated with a benign outcome.

Geometry and adhesion of extracellular domains of DC-SIGNR neck length variants analyzed by force-distance measurements.

Force-distance measurements have been used to examine differences in the interaction of the dendritic cell glycan-binding receptor DC-SIGN and the closely related endothelial cell receptor DC-SIGNR (L-SIGN) with membranes bearing glycan ligands. The results demonstrate that upon binding to membrane-anchored ligand, DC-SIGNR undergoes a conformational change similar to that previously observed for DC-SIGN. The results also validate a model for the extracellular domain of DC-SIGNR derived from crystallographic studies. Force measurements were performed with DC-SIGNR variants that differ in the length of the neck that result from genetic polymorphisms, which encode different numbers of the 23-amino acid repeat sequences that constitute the neck. The findings are consistent with an elongated, relatively rigid structure of the neck repeat observed in crystals. In addition, differences in the lengths of DC-SIGN and DC-SIGNR extracellular domains with equivalent numbers of neck repeats support a model in which the different dispositions of the carbohydrate-recognition domains in DC-SIGN and DC-SIGNR result from variations in the sequences of the necks.

Tubular carcinoma of the breast: further evidence to support its excellent prognosis.

PURPOSE Although tubular carcinoma (TC) is known to have a favorable prognosis, it is still unknown whether this subtype represents a distinct type of breast carcinoma or whether it behaves like other low-grade luminal A-type breast carcinomas. METHODS In this study, we performed a retrospective analysis of a large well-characterized series of breast cancers (2,608 carcinomas) to assess the clinicopathologic and molecular features and prognostic value of TC compared with grade 1 ductal carcinomas of the breast. Results When compared with grade 1 ductal carcinoma (n = 212), TC (n = 102) was more likely to be detected on mammographic screening, had smaller median size, and less frequently showed lymphovascular invasion. Compared with grade 1 ductal carcinoma, TC was associated with longer disease-free survival (chi(2) = 13.25, P < .001) and breast cancer-specific survival (chi(2) = 8.8, P = .003). In this study, none of the patients with TC developed distant metastasis or died from the disease without an intervening recurrence as invasive carcinoma of different histologic type. CONCLUSION We conclude that the biologic behavior of TC is excellent and is more favorable than that of grade 1 ductal carcinoma. Patients with TC may be at risk of developing second primary carcinomas in the contralateral breast, which may be of higher grade and poorer potential prognostic outcome. In addition, patients with TC seem to have a close to normal life expectancy, and as a consequence, adjuvant systemic therapy may not be justified in their routine management.

Binding-site geometry and flexibility in DC-SIGN demonstrated with surface force measurements.

The dendritic cell receptor DC-SIGN mediates pathogen recognition by binding to glycans characteristic of pathogen surfaces, including those found on HIV. Clustering of carbohydrate-binding sites in the receptor tetramer is believed to be critical for targeting of pathogen glycans, but the arrangement of these sites remains poorly understood. Surface force measurements between apposed lipid bilayers displaying the extracellular domain of DC-SIGN and a neoglycolipid bearing an oligosaccharide ligand provide evidence that the receptor is in an extended conformation and that glycan docking is associated with a conformational change that repositions the carbohydrate-recognition domains during ligand binding. The results further show that the lateral mobility of membrane-bound ligands enhances the engagement of multiple carbohydrate-recognition domains in the receptor oligomer with appropriately spaced ligands. These studies highlight differences between pathogen targeting by DC-SIGN and receptors in which binding sites at fixed spacing bind to simple molecular patterns.

Histologic grading is an independent prognostic factor in invasive lobular carcinoma of the breast.

UNLABELLED: Invasive lobular carcinoma (ILC) comprises approximately 5-15% of breast cancers and appears to have a distinct biology. As it is less common than invasive ductal carcinoma, few studies of large size have addressed the value of assessment of histologic grade in ILC. METHODS: This study is based on a large and well-characterised consecutive series of breast cancer (4,987 cases), from a single institution, with a long-term follow-up to assess the prognostic value of routine assessment of histologic grade in ILC. Histologic grade and other clinicopathological data were available in 517 pure ILC cases. A panel of biomarkers was also available for 215 cases. RESULTS: The majority of ILC was of classical and mixed lobular variants (89%). Most ILC cases were moderately differentiated (grade 2) tumours (76%), while a small proportion of tumours were either grade 1 or 3 tumours (12% each). There were positive associations between histologic grade and other clinicopathological variables of poor prognosis such as larger size, positive lymph node, vascular invasion, oestrogen receptor and androgen receptor negativity and p53 positivity. Multivariate analyses showed that histologic grade is an independent predictor of shorter breast cancer specific survival and disease free interval. CONCLUSION: Histologic grade of ILC, as assessed by the Nottingham grading system, provides a strong predictor of outcome in patients with invasive lobular carcinoma of the breast and should be provided routinely in pathology reports.