Microfluidic Sample Preparation Methods for the Analysis of Milk Contaminants

In systems for food analysis, one of the major challenges is related to the quantification of specific species into the complex chemical and physical composition of foods, that is, the effect of "matrix"; the sample preparation is often the key to a successful application of biosensors to real measurements but little attention is traditionally paid to such aspects in sensor research. In this critical review, we discuss several microfluidic concepts that can play a significant role in sample preparation, highlighting the importance of sample preparation for efficient detection of food contamination. As a case study, we focus on the challenges related to the detection of aflatoxinM1in milk and we evaluate possible approaches based on inertial microfluidics, electrophoresis, and acoustic separation, compared with traditional laboratory and industrial methods for phase separation as a baseline of thrust and well-established techniques

Suceder ou ceder? : um estudo exploratorio das relacoes entre empresa familiar, herdeiras e processo sucessorio

O presente trabalho busca elucidar o processo sucessório em empresas de constituição familiar sob a ótica, a percepção e as expectativas de suas herdeiras, abordando não só o processo sucessório em si, mas também questões relativas à dinâmica da família, a relação entre a familia e a empresa e a herdeira na empresa familiar. Uma vez que a sucessão de herdeiras na empresa familiar é ainda um assunto pouco pesquisado, optou-se pelo estudo de caso com método de investigação, por sua maior flexibilidade e por ser o método mais indicado para pesquisas exploratórias. Foram examinados dezoito casos de herdeiras em onze empresas familiares gaúchas. Os resultados da pesquisa foram analisados sob três aspectos básicos: a empresa versus a famma, a situação da herdeira na empresa familiar, e a sucessão propriamente dita.Foi possível concluir por meio deste trabalho que a sucessão de mulheres na empresa familiar ainda sofrerá alterações significativas, uma vez que não está relacionada unicamente a questões administrativas, mas tamoom a questões psicossociais. O tema é fortemente influenciado por aspectos tais como: os tipos diferentes de herdeiras, a relação entre a empresa e a família, a falta de planejamento no processo sucessório, a cultura patriarcal, o conflito entre o trabalho domestico e o trabalho profissional, relações de poder, entre outros.The purpo:se o f this study was to explore and analyze the succession process in the family business from the viewpoint of the female heirs, looking not only into the succession process itself but also in issues such as the family dynamics, the relation between the family and the company, and the heirs in the family bussiness. As the succession of female heirs is still an emerging topic, a case study has been carried out, not only due to the fact that this method of investigation presents a higher flex:ibility but also because this research deals with an issue which is still being developed. Eigtheen cases have been examined of female heirs from eleven familiy enterprises in the estate of Rio Grande do Sul, Brazil. The results of this research were analised under three basic aspects: the family versus the company, the situation of the female heir in the family business and the succession process itself. By means of this case study, it was possible to conclude that the succession process of female heirs is still going to cbange in some aspects, as it is related not only to organizational issues, but also to social and cultural ones. The issue is highly influenced by aspects such as: the different kinds ofheirs, the relationship between the family business and the family, the lack of planning the succession process, the patriarchal culture, the conflit between the domestic and the professional work and the power relations, among others

A Smart Watch with Embedded Sensors to Recognize Objects, Grasps and Forearm Gestures

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Use of Radium-223 Dichloride in Patients With Osteonecrosis of the Jaw Induced by Zoledronic Acid: Report of 2 Cases.

Bisphosphonates, a group of inorganic pyrophosphate analogues that prevent the loss of bone density, are commonly used in patients with bone metastases; the calcium-mimetic a-emitter radium-223 dichloride (Ra223) is a bone-targeting therapy used in patients with metastatic castration-resistant prostate cancer (mCRPC)-related bone metastases. Both treatments reduce pain and disability; Ra223 is associated with significantly improved overall survival in mCRPC. Patients who receive bisphosphonate therapy are at risk of developing osteonecrosis of the jaw, especially in those who do not undergo an accurate oral evaluation and sanitation before the beginning of therapy, and in patients who present with conditions that facilitate the development of this problem, such as inadequate oral and dental care, lack of prophylactic antimicrobial mouth rinsing, patient comorbidity, or suboptimal suturing after tooth extraction. Although there is possible synergism between bisphosphonates and Ra223 therapy, there is no consensus about the use of Ra223 in patients with previous/current osteonecrosis of the jaw induced by zoledronic acid. However, our experience suggests that Ra223 therapy might not be contraindicated in patients with osteonecrosis of the jaw induced by zoledronic acid if an appropriate multidisciplinary approach is followed, and we report 2 cases of patients with current or previous osteonecrosis of the jaw induced by zoledronic acid, who were treated with Ra223 for mCRPCrelated bone metastases. Multidisciplinary management, including accurate clinical and radiological evaluation before beginning therapy with Ra223, together with oral sanitation and periodic controls during treatment, allowed successful administration of Ra223 while reducing side effects, with absent or minimal worsening of osteonecrosis

Stereotactic radiotherapy of pancreatic cancer: A systematic review on pain relief

Locally advanced pancreatic carcinoma (LAPC) has a poor prognosis and the purpose of treatment is survival prolongation and symptom palliation. Radiotherapy has been reported to reduce pain in LAPC. Stereotactic RT (SBRT) is considered as an emerging radiotherapy technique able to achieve high local control rates with acceptable toxicity. However, its role in pain palliation is not clear. To review the impact on pain relief with SBRT in LAPC patients, a literature search was performed on PubMed, Scopus, and Embase (January 2000\u2013December 2017) for prospective and retrospective articles published in English. Fourteen studies (479 patients) reporting the effect of SBRT on pain relief were finally included in this analysis. SBRT was delivered with both standard and/or robotic linear accelerators. The median prescribed SBRT doses ranged from 16.5 to 45 Gy (median: 27.8 Gy), and the number of fractions ranged from 1 to 6 (median: 3.5). Twelve of the 14 studies reported the percentage of pain relief (in patients with pain at presentation) with a global overall response rate (complete and partial response) of 84.9% (95% CI, 75.8%\u201391.5%), with high heterogeneity (Q2 test: P<0.001; I2=83.63%). All studies reported toxicity data. Acute and late toxicity (grade 653) rates were 3.3%\u201318.0% and 6.0%\u20138.2%, respectively. Reported gastrointestinal side effects were duodenal obstruction/ ulcer, small bowel obstruction, duodenal bleeding, hemorrhage, and gastric perforation. SBRT achieves pain relief in most patients with pancreatic cancer with an acceptable gastrointestinal toxicity rate. Further prospective studies are needed to define optimal dose/fractionation and the best systemic therapies modality integration to reduce toxicity and improve the palliative outcome. Finally, the quality of life and, particularly, pain control should be considered as an endpoint in all future trials on this emerging treatment technique

Patient-Reported Outcomes After Swallowing (SWOARs)-Sparing IMRT in Head and Neck Cancers: Primary Results from a Prospective Study Endorsed by the Head and Neck Study Group (HNSG) of the Italian Association of Radiotherapy and Clinical Oncology (AIRO)

Objectives To prospectively investigate changes in M.D. Anderson Dysphagia Inventory (MDADI) scores in patients affected by naso- and oropharynx cancer after definitive radiochemotherapy (ChemoRT) using swallowing organs at risk (SWOARs)-sparing IMRT. Methods MDADI questionnaires were collected at baseline and at 6 and 12 months after treatment. MDADI scores were categorized as follows: >= 80 "optimal," 80-60 "adequate," < 60 "poor" deglutition-related quality of life (QoL) group, and dichotomized as "optimal" vs "adequate/poor" for the analysis. A mean MDADI composite (MDADI-C) change of 10 points was considered as minimal clinically important difference (MCID). Results Sixty-three patients were enrolled of which 47 were considered for the analysis. At baseline, 26 (55%) were "optimal" and 21 (45%) were "adequate/poor." The mean baseline MDADI-C score was 93.6 dropping to 81 at 6 months (p = 0.013) and slightly rising to 85.5 at 12 months (p = 0.321) for the "optimal" group. Indeed, the mean baseline MDADI-C score was 64.3 rising to 77.5 at 6 months (p = 0.006) and stabilizing at 76 at 12 months (p = 0.999) for the "adequate/poor" group. A statistically significant but not clinically relevant worsening of the MDADI-C score was reported for the "optimal" group, whereas both a statistically significant and clinically meaningful improvement of the MDADI-C score were reported for the "adequate/poor" group from before to post-treatment. Conclusion Our results suggest a doubly clinical benefit of dose optimization to SWOARs to minimize the RT sequalae in patients with a baseline "optimal" deglutition-related QoL and to recover from cancer dysphagia in those with a baseline "adequate/poor" deglutition-related QoL

An analysis of clinical, surgical, pathological and molecular characteristics of endometrial cancer according to mismatch repair status. A multidisciplinary approach

Since 2016, our hospital has applied tumor testing with immunohistochemistry (IHC) in endometrial cancer in order to detect mutations of mismatch repair genes (MMR). All cases with MMR deficiency proteins expression are sent for genetic testing, except those with MLH1 protein deficiency, in which case genetic testing is performed if negative for promoter hypermethylation. The primary aim of this study was to investigate the ability of our algorithm to identify Lynch syndrome (LS). The Secondary aims were to investigate the relationship between MMR status and clinicopathological features and prognosis of primary endometrial cancer (EC). From January 2016 to December 2018, 239 patients with EC were retrospectively analyzed and subdivided according to MMR status. Patients were divided in three groups: MMR proficient, LS and Lynch-like cancer (LLC). LS was characterized by a lower age and BMI, more use of contraceptive and less use of hormonal replacement therapy, nulliparity and a trend versus a better prognosis. LLC appeared more related to MMR proficient than LS and exhibited a more aggressive behavior. Our multidisciplinary approach permitted a correct diagnosis of germline mutation in patients with newly diagnosis EC and it confirmed clinicopathologic and prognostic characteristics of LS

The tissue-type plasminogen activator-plasminogen activator inhibitor 1 complex promotes neurovascular injury in brain trauma: evidence from mice and humans

The neurovascular unit provides a dynamic interface between the circulation and central nervous system. Disruption of neurovascular integrity occurs in numerous brain pathologies including neurotrauma and ischaemic stroke. Tissue plasminogen activator is a serine protease that converts plasminogen to plasmin, a protease that dissolves blood clots. Besides its role in fibrinolysis, tissue plasminogen activator is abundantly expressed in the brain where it mediates extracellular proteolysis. However, proteolytically active tissue plasminogen activator also promotes neurovascular disruption after ischaemic stroke; the molecular mechanisms of this process are still unclear. Tissue plasminogen activator is naturally inhibited by serine protease inhibitors (serpins): plasminogen activator inhibitor-1, neuroserpin or protease nexin-1 that results in the formation of serpin:protease complexes. Proteases and serpin:protease complexes are cleared through high-affinity binding to low-density lipoprotein receptors, but their binding to these receptors can also transmit extracellular signals across the plasma membrane. The matrix metalloproteinases are the second major proteolytic system in the mammalian brain, and like tissue plasminogen activators are pivotal to neurological function but can also degrade structures of the neurovascular unit after injury. Herein, we show that tissue plasminogen activator potentiates neurovascular damage in a dose-dependent manner in a mouse model of neurotrauma. Surprisingly, inhibition of activity following administration of plasminogen activator inhibitor-1 significantly increased cerebrovascular permeability. This led to our finding that formation of complexes between tissue plasminogen activator and plasminogen activator inhibitor-1 in the brain parenchyma facilitates post-traumatic cerebrovascular damage. We demonstrate that following trauma, the complex binds to low-density lipoprotein receptors, triggering the induction of matrix metalloproteinase-3. Accordingly, pharmacological inhibition of matrix metalloproteinase-3 attenuates neurovascular permeability and improves neurological function in injured mice. Our results are clinically relevant, because concentrations of tissue plasminogen activator: plasminogen activator inhibitor-1 complex and matrix metalloproteinase-3 are significantly elevated in cerebrospinal fluid of trauma patients and correlate with neurological outcome. In a separate study, we found that matrix metalloproteinase-3 and albumin, a marker of cerebrovascular damage, were significantly increased in brain tissue of patients with neurotrauma. Perturbation of neurovascular homeostasis causing oedema, inflammation and cell death is an important cause of acute and long-term neurological dysfunction after trauma. A role for the tissue plasminogen activator-matrix metalloproteinase axis in promoting neurovascular disruption after neurotrauma has not been described thus far. Targeting tissue plasminogen activator: plasminogen activator inhibitor-1 complex signalling or downstream matrix metalloproteinase-3 induction may provide viable therapeutic strategies to reduce cerebrovascular permeability after neurotraum

PAK6 phosphorylates 14-3-3γ to regulate steady state phosphorylation of LRRK2

Mutations in Leucine-rich repeat kinase 2 (LRRK2) are associated with Parkinson's disease (PD) and, as such, LRRK2 is considered a promising therapeutic target for age-related neurodegeneration. Although the cellular functions of LRRK2 in health and disease are incompletely understood, robust evidence indicates that PD-associated mutations alter LRRK2 kinase and GTPase activities with consequent deregulation of the downstream signaling pathways. We have previously demonstrated that one LRRK2 binding partner is P21 (RAC1) Activated Kinase 6 (PAK6). Here, we interrogate the PAK6 interactome and find that PAK6 binds a subset of 14-3-3 proteins in a kinase dependent manner. Furthermore, PAK6 efficiently phosphorylates 14-3-3γ at Ser59 and this phosphorylation serves as a switch to dissociate the chaperone from client proteins including LRRK2, a well-established 14-3-3 binding partner. We found that 14-3-3γ phosphorylated by PAK6 is no longer competent to bind LRRK2 at phospho-Ser935, causing LRRK2 dephosphorylation. To address whether these interactions are relevant in a neuronal context, we demonstrate that a constitutively active form of PAK6 rescues the G2019S LRRK2-associated neurite shortening through phosphorylation of 14-3-3γ. Our results identify PAK6 as the kinase for 14-3-3γ and reveal a novel regulatory mechanism of 14-3-3/LRRK2 complex in the brain

Impact of different chemotherapy regimens on intestinal mucosal injury assessed with bedside ultrasound: a study in 213 AML patients

IntroductionNeutropenic enterocolitis (NEC) is a life-threatening complication reported in patients with acute myeloid leukemia (AML) following chemotherapy (CHT). Intensive induction and consolidation CHT may damage intestinal mucosa leading to a NEC episode (NECe). NEC reported mortality may be up to 30-60%. Early US-guided bed-side diagnosis and prompt treatment may substantially improve the survival. An emerging worldwide concern is the intestinal colonization by multi-drug-resistant bacteria especially when patients are exposed to chemotherapy regimens potentially correlated to mucosal damage. MethodsIn our study we prospectively enrolled all AML patients admitted in our leukemia unit to receive intensive induction and consolidation chemotherapy and experiencing chemotherapy-induced-neutropenia (CHTN). Results and discussionOverall, we enrolled N=213 patients from 2007 to March 2023. We recorded N=465 CHTN, and N=42 NECe (9.0% incidence). The aim of our study was to assess which chemotherapy regimens are more associated with NEC. We found that ALM1310, followed by 7 + 3 (daunorubicin), 7 + 3 (idarubicin), 5 + 3 + 3 (cytarabine, etoposide, idarubicin), and AML1310 (consolidation) were associated with a statistically higher incidence of NEC. We did not detect NEC episodes in patients treated with CPX-351, 5 + 2 (cytarabine, idarubicine), and high-dose cytarabine. Thus, we found that cytarabine could determine mucosal damage when associated with an anthracycline but not if delivered either alone or as dual-drug liposomal encapsulation of daunorubicin/cytarabine. We also describe NEC mortality, symptoms at diagnosis, intestinal sites involvement, and prognostic significance of bowel wall thickening