Silk fibroin microgels as a platform for cell microencapsulation

: Cell microencapsulation has been utilized for years as a means of cell shielding from the external environment while facilitating the transport of gases, general metabolites, and secretory bioactive molecules at once. In this light, hydrogels may support the structural integrity and functionality of encapsulated biologics whereas ensuring cell viability and function and releasing potential therapeutic factors once in situ. In this work, we describe a straightforward strategy to fabricate silk fibroin (SF) microgels (µgels) and encapsulate cells into them. SF µgels (size ≈ 200 µm) were obtained through ultrasonication-induced gelation of SF in a water-oil emulsion phase. A thorough physicochemical (SEM analysis, and FT-IR) and mechanical (microindentation tests) characterization of SF µgels were carried out to assess their nanostructure, porosity, and stiffness. SF µgels were used to encapsulate and culture L929 and primary myoblasts. Interestingly, SF µgels showed a selective release of relatively small proteins (e.g., VEGF, molecular weight, MW = 40 kDa) by the encapsulated primary myoblasts, while bigger (macro)molecules (MW = 160 kDa) were hampered to diffusing through the µgels. This article provided the groundwork to expand the use of SF hydrogels into a versatile platform for encapsulating relevant cells able to release paracrine factors potentially regulating tissue and/or organ functions, thus promoting their regeneration

Appendiceal goblet cell carcinoma has marginal advantages from perioperative chemotherapy: a population-based study with an entropy balancing analysis

PurposeThe aim is to clarify the use of perioperative chemotherapy in resectable goblet cell carcinoma (GCC).MethodsA retrospective study was carried out based on the Surveillance, Epidemiology, and End Results study. The population was divided: into patients who received only radical surgery (group A) and those who received radical surgery plus chemotherapy (group B). An entropy balancing was carried out to correct the imbalance between the two groups. Two models were generated. Model 1 contained only high-risk patients: group B and a "virtual" group A with similar characteristics. Model 2 included only low-risk patients: group A and "virtual" group B with identical attributes. The efficacy of entropy balancing was evaluated with the d value. The overall survival was compared and reported with Hazard Ratio (HR) within a confidence interval of 95% (95 CI).ResultsThe groups A and B were imbalanced for tumor size (d = 0.392), T (d = 1.128), N (d = 1.340), M (d = 1.456), mean number of positive lymph nodes (d = 0.907), and LNR (d = 0.889). Before the balancing, the risk of death was higher in group B than in A (4.3; 2.5 to 7.4). After reweighting, all large differences were eliminated (d < 0.200). In high-risk patients, the risk of death was higher in patients who underwent surgery alone than those who received perioperative chemotherapy (HR 0.5; 0.2 to 1.3) without statistical significance (p = 0.187). In low-risk patients, the risk of death was similar (HR 1.1; 0.3 to 3.3).ConclusionPerioperative chemotherapy could provide some marginal advantages to high-risk patients

Multitarget drug design strategy in Alzheimer’s disease: focus on cholinergic transmission and amyloid-β aggregation

Background: Alzheimer pathogenesis has been associated with a network of processes working simultaneously and synergistically. Over time, much interest has been focused on cholinergic transmission and its mutual interconnections with other active players of the disease. Besides the cholinesterase mainstay, the multifaceted interplay between nicotinic receptors and amyloid is actually considered to have a central role in neuroprotection. Thus, the multitarget drug-design strategy has emerged as a chance to face the disease network. Results: By exploiting the multitarget approach, the present study provides new molecules able to target the cholinergic pathway, by joining direct nicotinic receptor stimulation to acetylcholinesterase inhibition, and to inhibit Aβ aggregation. Conclusions: These new compounds emerged as a suitable starting point for a further optimization process

Survey of transfemoral amputee experience and priorities for the user-centered design of powered robotic transfemoral prostheses

BACKGROUND: Transfemoral amputees experience a complex host of physical, psychological, and social challenges, compounded by the functional limitations of current transfemoral prostheses. However, the specific relationships between human factors and prosthesis design and performance characteristics have not yet been adequately investigated. The present study aims to address this knowledge gap. METHODS: A comprehensive single-cohort survey of 114 unilateral transfemoral amputees addressed a broad range of demographic and clinical characteristics, functional autonomy, satisfaction and attitudes towards their current prostheses, and design priorities for an ideal transfemoral prosthesis, including the possibility of active assistance from a robotic knee unit. The survey was custom-developed based on several standard questionnaires used to assess motor abilities and autonomy in activities of daily living, prosthesis satisfaction, and quality of life in lower-limb amputees. Survey data were analyzed to compare the experience (including autonomy and satisfaction) and design priorities of users of transfemoral prostheses with versus without microprocessor-controlled knee units (MPKs and NMPKs, respectively), with a subsequent analyses of cross-category correlation, principal component analysis (PCA), cost-sensitivity segmentation, and unsupervised K-means clustering applied within the most cost-sensitive participants, to identify functional groupings of users with respect to their design priorities. RESULTS: The cohort featured predominantly younger (< 50 years) traumatic male amputees with respect to the general transfemoral amputee population, with pronounced differences in age distribution and amputation etiology (traumatic vs. non-traumatic) between MPK and NMPK groups. These differences were further reflected in user experience, with MPK users reporting significantly greater overall functional autonomy, satisfaction, and sense of prosthesis ownership than those with NMPKs, in conjunction with a decreased incidence of instability and falls. Across all participants, the leading functional priorities for an ideal transfemoral prosthesis were overall stability, adaptability to variable walking velocity, and lifestyle-related functionality, while the highest-prioritized general characteristics were reliability, comfort, and weight, with highly variable prioritization of cost according to reimbursement status. PCA and user clustering analyses revealed the possibility for functionally relevant groupings of prosthesis features and users, based on their differential prioritization of these features—with implications towards prosthesis design tradeoffs. CONCLUSIONS: This study’s findings support the understanding that when appropriately prescribed according to patient characteristics and needs in the context of a proactive rehabilitation program, advanced transfemoral prostheses promote patient mobility, autonomy, and overall health. Survey data indicate overall stability, modularity, and versatility as key design priorities for the continued development of transfemoral prosthesis technology. Finally, observed associations between prosthesis type, user experience, and attitudes concerning prosthesis ownership suggest both that prosthesis characteristics influence device acceptance and functional outcomes, and that psychosocial factors should be specifically and proactively addressed during the rehabilitation process. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s12984-021-00944-x

Evolving knowledge in surgical oncology of pancreatic cancer: from theory to clinical practice-a fifteen-year journey at a tertiary referral centre

Pancreatic ductal adenocarcinoma (PDAC) is an increasing disease having a poor prognosis. The aim of the present study was to evaluate the effect of different models of care for pancreatic cancer in a tertiary referral centre in the period 2006-2020. Retrospective study of patients with PDAC observed from January 2006 to December 2020. The demographic and clinical data, and data regarding the imaging techniques used, preoperative staging, management, survival and multidisciplinary tumour board (MDTB) evaluation were collected and compared in three different periods characterised by different organisation of pancreatic cancer services: period A (2006-2010); period B (2011-2015) and period C (2016-2020). One thousand four hundred seven patients were analysed: 441(31.3%) in period A; 413 (29.4%) in B and 553 (39.3%) in C. The proportion of patients increased significantly, from 31.3% to 39.3% (P = 0.032). Body mass index (P = 0.033), comorbidity rate (P = 0.002) and Karnofsky performance status (P &lt; 0.001) showed significant differences. Computed tomography scans (P &lt; 0.001), endoscopic ultrasound (P &lt; 0.001), fine needle aspiration, fine needle biopsy (P &lt; 0.001), and fluorodeoxyglucose-positron emission tomography/computed tomography (P &lt; 0.001) increased; contrast-enhanced ultrasound (P = 0.028) decreased. The cTNM was significantly different (P &lt; 0.001). The MDTB evaluation increased significantly (P &lt; 0.001). Up-front surgery and exploratory laparotomy decreased (P &lt; 0.001), neoadjuvant treatment increased (P &lt; 0.001). The present study showed the evolving knowledge in surgical oncology of pancreatic cancer at a tertiary referral centre over the time. The different models of care of pancreatic cancer, in particular the introduction of the MDTB and the institution of a pancreas unit to the decision-making process seemed to be influential

Papiloma vírus humano e a relação com o câncer de colo uterino / Human papillomavirus and the relationship with cervical cancer

O papilomavírus humano causa uma infecção sexualmente transmissível caracterizada pelo surgimento de verrugas, também chamadas de papilomas, nas regiões urogenital e úmidas do corpo. Este estudo trata de uma revisão narrativa da literatura, realizada por meio de busca em livros e artigos científicos com conteúdos acerca da temática.  Como resultado destaca-se que há mais de 100 tipos de vírus, porém apenas 40 infectam o trato genital sendo que os tipos 16 e 18 são os que apresentam potencial oncogênico para o câncer uterino. Mundialmente o câncer de colo de útero é o terceiro tipo de câncer mais predominante nas mulheres, sendo que no Brasil a região norte é a mais afetada. O diagnóstico dessa neoplasia pode ser realizado por meio de exames histológicos que utilizam a colposcopia, curetagem endocervical e biópsia de cone. Há ainda os exames de imagens que geralmente são usados para o estadiamento da metástase, isto é, o seu espalhamento através do corpo. Sem tratamento efetivo para o vírus, apenas as verrugas podem ser tratadas. O câncer, dependendo da evolução do tumor, tem como opção tratamento pela quimioterapia, cirurgia ou radioterapia. Considera-se que a prevenção do HPV ocorre pelo uso de vacina, tomada em duas doses, e pelo uso de preservativos com a ressalva de que eles não são 100% eficientes em todas as situações

Integrated clinicopathologic and molecular analysis of endometrial carcinoma: Prognostic impact of the new ESGO-ESTRO-ESP endometrial cancer risk classification and proposal of histopathologic algorithm for its implementation in clinical practice

IntroductionThe European Society of Gynecologic Oncology/European Society of Radiation Therapy and Oncology/European Society of Pathology (ESGO/ESTRO/ESP) committee recently proposed a new risk stratification system for endometrial carcinoma (EC) patients that incorporates clinicopathologic and molecular features. The aim of the study is to compare the new ESGO/ESTRO/ESP risk classification system with the previous 2016 recommendations, evaluating the impact of molecular classification and defining a new algorithm for selecting cases for molecular analysis to assign the appropriate risk class.MethodsThe cohort included 211 consecutive EC patients. Immunohistochemistry and next-generation sequencing were used to assign molecular subgroups of EC: POLE mutant (POLE), mismatch repair deficient (MMRd), p53 mutant (p53abn), and no specific molecular profile (NSMP).ResultsImmuno-molecular analysis was successful in all cases, identifying the four molecular subgroups: 7.6% POLE, 32.2% MMRd, 20.9% p53abn, and 39.3% NSMP. The recent 2020 guidelines showed a 32.7% risk group change compared with the previous 2016 classification system: the reassignment is due to POLE mutations, abnormal p53 expression, and a better definition of lymphovascular space invasion. The 2020 system assigns more patients to lower-risk groups (42.2%) than the 2016 recommendation (25.6%). Considering the 2020 risk classification system that includes the difference between “unknown molecular classification” and “known,” the integration of molecular subgroups allowed 6.6% of patients to be recategorized into a different risk class. In addition, the use of the proposed algorithm based on histopathologic parameters would have resulted in a 62.6% reduction in molecular analysis, compared to applying molecular classification to all patients.ConclusionApplication of the new 2020 risk classification integrating clinicopathologic and molecular parameters provided more accurate identification of low-and high-risk patients, potentially allowing a more specific selection of patients for post-operative adjuvant therapy. The proposed histopathologic algorithm significantly decreases the number of tests needed and could be a promising tool for cost reduction without compromising prognostic stratification

Combining Galantamine and Memantine in Multitargeted, New Chemical Entities Potentially Useful in Alzheimer’s Disease

Herein we report on a novel series of multitargeted compounds obtained by linking together galantamine and memantine. The compounds were designed by taking advantage of the crystal structures of acetylcholinesterase (AChE) in complex with galantamine derivatives. Sixteen novel derivatives were synthesized, using spacers of different lengths and chemical composition. The molecules were then tested as inhibitors of AChE and as binders of the N-methyl-d-aspartate (NMDA) receptor (NMDAR). Some of the new compounds were nanomolar inhibitors of AChE and showed micromolar affinities for NMDAR. All compounds were also tested for selectivity toward NMDAR containing the 2B subunit (NR2B). Some of the new derivatives showed a micromolar affinity for NR2B. Finally, selected compounds were tested using a cell-based assay to measure their neuroprotective activity. Three of them showed a remarkable neuroprotective profile, inhibiting the NMDA-induced neurotoxicity at subnanomolar concentrations (e.g., 5, named memagal, IC(50) = 0.28 nM)

"Delirium Day": A nationwide point prevalence study of delirium in older hospitalized patients using an easy standardized diagnostic tool

Background: To date, delirium prevalence in adult acute hospital populations has been estimated generally from pooled findings of single-center studies and/or among specific patient populations. Furthermore, the number of participants in these studies has not exceeded a few hundred. To overcome these limitations, we have determined, in a multicenter study, the prevalence of delirium over a single day among a large population of patients admitted to acute and rehabilitation hospital wards in Italy. Methods: This is a point prevalence study (called "Delirium Day") including 1867 older patients (aged 65 years or more) across 108 acute and 12 rehabilitation wards in Italian hospitals. Delirium was assessed on the same day in all patients using the 4AT, a validated and briefly administered tool which does not require training. We also collected data regarding motoric subtypes of delirium, functional and nutritional status, dementia, comorbidity, medications, feeding tubes, peripheral venous and urinary catheters, and physical restraints. Results: The mean sample age was 82.0 \ub1 7.5 years (58 % female). Overall, 429 patients (22.9 %) had delirium. Hypoactive was the commonest subtype (132/344 patients, 38.5 %), followed by mixed, hyperactive, and nonmotoric delirium. The prevalence was highest in Neurology (28.5 %) and Geriatrics (24.7 %), lowest in Rehabilitation (14.0 %), and intermediate in Orthopedic (20.6 %) and Internal Medicine wards (21.4 %). In a multivariable logistic regression, age (odds ratio [OR] 1.03, 95 % confidence interval [CI] 1.01-1.05), Activities of Daily Living dependence (OR 1.19, 95 % CI 1.12-1.27), dementia (OR 3.25, 95 % CI 2.41-4.38), malnutrition (OR 2.01, 95 % CI 1.29-3.14), and use of antipsychotics (OR 2.03, 95 % CI 1.45-2.82), feeding tubes (OR 2.51, 95 % CI 1.11-5.66), peripheral venous catheters (OR 1.41, 95 % CI 1.06-1.87), urinary catheters (OR 1.73, 95 % CI 1.30-2.29), and physical restraints (OR 1.84, 95 % CI 1.40-2.40) were associated with delirium. Admission to Neurology wards was also associated with delirium (OR 2.00, 95 % CI 1.29-3.14), while admission to other settings was not. Conclusions: Delirium occurred in more than one out of five patients in acute and rehabilitation hospital wards. Prevalence was highest in Neurology and lowest in Rehabilitation divisions. The "Delirium Day" project might become a useful method to assess delirium across hospital settings and a benchmarking platform for future surveys