IGFBP-3 inhibits Wnt signaling in metastatic melanoma cells.

In previous works, we have shown that insulin-like growth factor-binding protein-3 (IGFBP-3), a tissue and circulating protein able to bind to IGFs, decreases drastically in the blood serum of patients with diffuse metastatic melanoma. In agreement with the clinical data, recombinant IGFBP-3 was found to inhibit the motility and invasiveness of cultured metastatic melanoma cells and to prevent growth of grafted melanomas in mice. The present work was aimed at identifying the signal transduction pathways underlying the anti-tumoral effects of IGFBP-3. We show that the anti-tumoral effect of IGFBP-3 is due to inhibition of the Wnt pathway and depends upon the presence of CD44, a receptor protein known to modulate Wnt signaling. Once it has entered the cell, IGFBP-3 binds the Wnt signalosome interacting specifically with its component GSK-3β. As a consequence, the β-catenin destruction complex dissociates from the LRP6 Wnt receptor and GSK-3β is activated through dephosphorylation, becoming free to target cytoplasmic β-catenin which is degraded by the proteasomal pathway. Altogether, the results suggest that IGFBP-3 is a novel and effective inhibitor of Wnt signaling. As IGFBP-3 is a physiological protein which has no detectable toxic effects either on cultured cells or live mice, it might qualify as an interesting new therapeutic agent in melanoma, and potentially many other cancers with a hyperactive Wnt signaling

Behavioral disturbances in dementia and beyond: Time for a new conceptual frame?

Alzheimer\u2019s disease and vascular dementia are estimated to be the most common causes of dementia, although mixed dementia could represent the most prevalent form of dementia in older adults aged more than 80 years. Behavioral disturbances are common in the natural history of dementia. However, so far, there is a paucity of studies that investigated the causal association between behavioral psychological symptoms of dementia and dementia sub-types, due to the high heterogeneity of methodology, study design and type of clinical assessment. To understand the scant evidence on such a relevant clinical issue, it could be hypothesized that a new shifting paradigm could result in a better identification of the relationship between behavioral disturbances and dementia. This narrative review provides an update of evidence on the behavioral patterns associated with different dementia sub-types and offers a potential future perspective as common ground for the development of new translational studies in the field of behavioral disturbances in dementia and the appropriateness of psychoactive treatments

The water safety plan approach: Application to small drinking-water systems—case studies in salento (south italy)

none6noBackground: The quality of water for human consumption is an objective of fundamental importance for the defense of public health. Since the management of networks involves many problems of control and efficiency of distribution, the Water Safety Plan (WSP) was introduced to address these growing problems. Methods: WSP was applied to three companies in which the water resource assumes central importance: five water kiosks, a third-range vegetable processing company, and a residence and care institution. In drafting the plan, the terms and procedures designed and tested for the management of urban distribution systems were applied to safeguard the resource over time. Results: The case studies demonstrated the reliability of the application of the model even to small drinking-water systems, even though it involved a greater effort in analyzing the incoming water, the local intended use, and the possibilities for managing the containment of the dangers to which it is exposed. This approach demonstrates concrete effectiveness in identifying and mitigating the dangers of altering the quality of water. Conclusions: Thanks to the WSP applied to small drinking-water systems, we can move from management that is focused mainly on verifying the conformity of the finished product to the creation of a global risk assessment and management system that covers the entire water supply chain.openSerio F.; Martella L.; Imbriani G.; Idolo A.; Bagordo F.; De Donno A.Serio, F.; Martella, L.; Imbriani, G.; Idolo, A.; Bagordo, F.; De Donno, A

Duplex DNA from Sites of Helicase-Polymerase Uncoupling Links Non-B DNA Structure Formation to Replicative Stress

BACKGROUND: Replication impediments can produce helicase-polymerase uncoupling allowing lagging strand synthesis to continue for as much as 6 kb from the site of the impediment. MATERIALS AND METHODS: We developed a cloning procedure designed to recover fragments from lagging strand near the helicase halt site. RESULTS: A total of 62% of clones from a p53-deficient tumor cell line (PC3) and 33% of the clones from a primary cell line (HPS-19I) were within 5 kb of a G-quadruplex forming sequence. Analyses of a RACK7 gene sequence, that was cloned multiple times from the PC3 line, revealed multiple deletions in region about 1 kb from the cloned region that was present in a non-B conformation. Sequences from the region formed G-quadruplex and i-motif structures under physiological conditions. CONCLUSION: Defects in components of non-B structure suppression systems (e.g. p53 helicase targeting) promote replication-linked damage selectively targeted to sequences prone to G-quadruplex and i-motif formation

Genetic heterogeneity of porcine enteric caliciviruses identified from diarrhoeic piglets

Enteric caliciviruses (noroviruses and sapoviruses) are responsible for the majority of non-bacterial gastroenteritis in humans of all age groups. Analysis of the polymerase and capsid genes has provided evidence for a huge genetic diversity, but the understanding of their ecology is limited. In this study, we investigated the presence of porcine enteric caliciviruses in the faeces of piglets with diarrhoea. A total of 209 samples from 118 herds were analyszd and calicivirus RNA was detected by RT-PCR in 68 sample (32.5%) and in 46 herds (38.9%), alone or in mixed infection with group A and C rotaviruses. Sequence and phylogenetic analysis of the calicivirus-positive samples characterized the majority as genogroup III (GGIII) sapoviruses. Unclassified caliciviruses, distantly related to the representatives of the other sapovirus genogroups, were identified in five herds, while one outbreak was associated with a porcine sapovirus related genetically to human GGII and GGIV sapovirus strains. By converse, norovirus strains were not detected. Altogether, these data suggest the epidemiological relevance of porcine enteric caliciviruses and suggest a role in the etiology of piglets diarrhoe

Point-of-care testing allows successful simultaneous screening of sickle cell disease, HIV, and tuberculosis for households in rural Guinea-Bissau, West Africa

Diagnosis of noncommunicable genetic diseases like sickle cell disease (SCD) and com municable diseases such as human immunodeficiency virus (HIV) or tuberculosis (TB) is often difficult in rural areas of Africa due to the lack of infrastructures, trained staff, or capacity to involve families living in remote areas. The availability of point-of-care (POC) tests for the above diseases offers the opportunity to build joint programs to tackle all conditions. We report successful simultaneous screening of SCD, HIV, and TB utilizing POC tests in 898 subjects in Fanhe, in rural Guinea-Bissau. Adherence was 100% and all diagnosed subjects were enrolled in care program

Sexual function after vaginal erbium laser: the results of a large, multicentric, prospective study.

The aim of this multicentric, prospective study was to evaluate the effects of vaginal erbium laser (VEL-SMOOTH®) on sexual function in postmenopausal women suffering from the genitourinary syndrom..

Guide-wire replacement of a mini-midline catheter with a central venous catheter: A retrospective study on 63 cases

Background: Achieving a reliable venous access in a particular subset of patients and/or in emergency settings can be challenging and time-consuming. Furthermore, many hospitalized patients do not meet the criteria for central venous catheter positioning, unless an upgrade of the treatment is further needed. The mini-midline catheter has already showed to be reliable and safe as a stand-alone device, since it is easily and rapidly inserted and can indwell up to 1 month. Methods: In this further case series, we retrospectively evaluated data from 63 patients where a previously inserted mini-midline catheter was upgraded to a central venous catheter (the devices inserted in the arm replaced by peripherally inserted central catheter and others inserted “off-label” in the internal jugular replaced by single lumen centrally inserted central catheter), being used as introducer for the Seldinger guidewire. Results: The guidewire replacement was been made even early (after 1 day) or late (more than 10 days), usually following a need for an upgrade in treatment. No early or late complications were reported. Conclusion: According to the preliminary data we collected, this converting procedure seems to be feasible and risk-free, since neither infectious nor thrombotic complications were reported

Possible human-to-dog transmission of SARS-CoV-2, Italy, 2020

We detected severe acute respiratory syndrome coronavirus 2 in an otherwise healthy poodle living with 4 family members who had coronavirus disease. We observed antibodies in serum samples taken from the dog, indicating seroconversion. Full-length genome sequencing showed that the canine and human viruses were identical, suggesting human-to-animal transmission

Phase II study of capecitabine-based concomitant chemoradiation followed by durvalumab as a neoadjuvant strategy in locally advanced rectal cancer: the PANDORA trial

Background: This study investigated the efficacy of chemoradiotherapy (CRT) followed by durvalumab as neoadjuvant therapy of locally advanced rectal cancer.Patients and methods: The PANDORA trial is a prospective, phase II, open-label, single-arm, multicenter study aimed at evaluating the efficacy and safety of preoperative treatment with durvalumab (1500 mg every 4 weeks for three administrations) following long-course radiotherapy (RT) plus concomitant capecitabine (5040 cGy RT in 25-28 fractions over 5 weeks and capecitabine administered at 825 mg/m2 twice daily). The primary endpoint was the pathological complete response (pCR) rate; secondary endpoints were the proportion of clinical complete remissions and safety. The sample size was estimated assuming a null pCR proportion of 0.15 and an alternative pCR proportion of 0.30 (a = 0.05, power = 0.80). The proposed treatment could be considered promising if >= 13 pCRs were observed in 55 patients (EudraCT: 2018-004758-39; NCT04083365).Results: Between November 2019 and August 2021, 60 patients were accrued, of which 55 were assessable for the study's objectives. Two patients experienced disease progression during treatment. Nineteen out of 55 eligible patients achieved a pCR (34.5%, 95% confidence interval 22.2% to 48.6%). Regarding toxicity related to durvalumab, grade 3 adverse events (AEs) occurred in four patients (7.3%) (diarrhea, skin toxicity, transaminase increase, lipase increase, and pancolitis). Grade 4 toxicity was not observed. In 20 patients (36.4%), grade 1-2 AEs related to durvalumab were observed. The most common were endocrine toxicity (hyper/hypothyroidism), dermatologic toxicity (skin rash), and gastrointestinal toxicity (transaminase increase, nausea, diarrhea, constipation).Conclusion: This study met its primary endpoint showing that CRT followed by durvalumab could increase pCR with a safe toxicity profile. This combination is a promising, feasible strategy worthy of further investigation