Dynamic Compensation of a Piezoelectric Accelerometer Obtained through a General Probabilistic Approach.

Dynamic compensation is the (partial) correction of the measurement signals for the effects due to bandwidth limitations of measurement systems and constitutes a research topic in dynamic measurement. The dynamic compensation of an accelerometer is here considered, as obtained by a method that directly comes from a general probabilistic model of the measurement process. Although the application of the method is simple, the analytical development of the corresponding compensation filter is quite complex and had been previously developed only for first-order systems, whilst here a second-order system is considered, thus moving from a scalar to a vector problem. The effectiveness of the method has been tested both through simulation and by a dedicated experiment. Both tests have shown the capability of the method of significantly improve the performance of the measurement system when dynamic effects are more prevalent than additive observation noise.

Improvement in the Post-Processing of Wave Buoy Data Driven by the Needs of a National Coast and Sea Monitoring Agency.

Technological development in terms of the power requirement for data acquisition and processing opens new perspectives in the field of environmental monitoring. Near real-time data flow about the sea condition and a possible direct interface with applications and services devoted to marine weather networks would have a significant impact on several aspects, such as, for example, safety and efficiency. In this scenario, the needs of buoy networks have been analyzed, and the estimation of directional wave spectra from buoys' data has been deeply investigated. Two methods have been implemented, namely the truncated Fourier series and the weighted truncated Fourier series, and they have been tested by both simulated and real experimental data, representative of typical Mediterranean Sea conditions. From simulation, the second method proved to be more efficient. From the application to real case studies, it emerged that it works effectively in real conditions, as confirmed by parallel meteorological observations. The estimation of the main propagation direction was possible with a small uncertainty of a few degrees, yet the method exhibits a limited directional resolution, which suggests the need for undertaking further studies, briefly addressed in the conclusions.

Germline Variants in MLH1 and ATM Genes in a Young Patient with MSI-H in a Precancerous Colonic Lesion.

Lynch syndrome (LS) is an autosomal dominant inherited disorder that primarily predisposes individuals to colorectal and endometrial cancer. It is associated with pathogenic variants in DNA mismatch repair (MMR) genes. In this study, we report the case of a 16-year-old boy who developed a precancerous colonic lesion and had a clinical suspicion of LS. The proband was found to have a somatic MSI-H status. Analysis of the coding sequences and flanking introns of the MLH1 and MSH2 genes by Sanger sequencing led to the identification of the variant of uncertain significance, namely, c.589-9_589-6delGTTT in the MLH1 gene. Further investigation revealed that this variant was likely pathogenetic. Subsequent next-generation sequencing panel analysis revealed the presence of two variants of uncertain significance in the ATM gene. We conclude that the phenotype of our index case is likely the result of a synergistic effect of these identified variants. Future studies will allow us to understand how risk alleles in different colorectal-cancer-prone genes interact with each other to increase an individual's risk of developing cancer.

Sea Spectral Estimation Using ARMA Models.

This paper deals with the spectral estimation of sea wave elevation time series by means of ARMA models. To start, the procedure to estimate the ARMA coefficients, based on the use of the Prony's method applied to the auto-covariance series, is presented. Afterwards, an analysis on how the parameters involved in the ARMA reconstruction procedure-for example, the signal time length, the number of poles and data used-affect the spectral estimates is carried out, providing evidence on their effect on the accuracy of results. This allowed us to provide guidelines on how to set these parameters in order to make the ARMA model as accurate as possible. The paper focuses on mono-modal sea states. Nevertheless, examples also related to bi-modal sea states are discussed.

Filtering Biomechanical Signals in Movement Analysis.

Biomechanical analysis of human movement is based on dynamic measurements of reference points on the subject's body and orientation measurements of body segments. Collected data include positions' measurement, in a three-dimensional space. Signal enhancement by proper filtering is often recommended. Velocity and acceleration signal must be obtained from position/angular measurement records, needing numerical processing effort. In this paper, we propose a comparative filtering method study procedure, based on measurement uncertainty related parameters' set, based upon simulated and experimental signals. The final aim is to propose guidelines to optimize dynamic biomechanical measurement, considering the measurement uncertainty contribution due to the processing method. Performance of the considered methods are examined and compared with an analytical signal, considering both stationary and transient conditions. Finally, four experimental test cases are evaluated at best filtering conditions for measurement uncertainty contributions.

Investigation on Spectrum Estimation Methods for Bimodal Sea State Conditions.

The reliable monitoring of sea state parameters is a key factor for weather forecasting, as well as for ensuring the safety and navigation of ships. In the current analysis, two spectrum estimation techniques, based on the Welch and Thomson methods, were applied to a set of random wave signals generated from a theoretical wave spectrum obtained by combining wind sea and swell components with the same prevailing direction but different combinations of significant wave heights, peak periods, and peak enhancement factors. A wide benchmark study was performed to systematically apply and compare the two spectrum estimation methods. In this respect, different combinations of wind sea spectra, corresponding to four grades of the Douglas Scale, were combined with three swell spectra corresponding to different swell categories. The main aim of the benchmark study was to systematically investigate the effectiveness of the Welch and Thomson methods in terms of spectrum restitution and the assessment of sea state parameters. The spectrum estimation methods were applied to random wave signals with different durations, namely 600 s (short) and 3600 s (long), to investigate how the record length affected the assembled sea state parameters, which, in turn, were assessed by the nonlinear least square method. Finally, based on the main outcomes of the benchmark study, some suggestions are provided to select the most suitable spectrum reconstruction method and increase the effectiveness of the assembled sea state parameters.

Measurement of Sea Waves.

Sea waves constitute a natural phenomenon with a great impact on human activities, and their monitoring is essential for meteorology, coastal safety, navigation, and renewable energy from the sea. Therefore, the main measurement techniques for their monitoring are here reviewed, including buoys, satellite observation, coastal radars, shipboard observation, and microseism analysis. For each technique, the measurement principle is briefly recalled, the degree of development is outlined, and trends are prospected. The complementarity of such techniques is also highlighted, and the need for further integration in local and global networks is stressed.

Comparison of Spectrum Estimation Methods for the Accurate Evaluation of Sea State Parameters.

The monitoring of sea state conditions, either for weather forecasting or ship seakeeping analysis, requires the reliable assessment of the sea spectra encountered by the ship, either as a final result or intermediate step for the measurement of the relevant wave-motion parameters. In current analyses, different spectrum estimation methods, namely the Welch, Thomson and ARMA models, have been applied and compared based on a set of random wave signals, with different durations, representative of several sea state conditions. Subsequently, two sea spectrum reconstruction techniques were described and applied in order to detect the main sea state parameters, namely the significant wave height, the mean wave period and the spectrum peak enhancement factor. The performances of both spectral analysis and sea state reconstruction methods are discussed in order to provide some preliminary guidelines for practical application purposes. In this respect, based on current results, the Welch and Thomson methods seem to be the most promising techniques, combined with the nonlinear least-square reconstruction technique.

A Negative Allosteric Modulator of WNT Receptor Frizzled 4 Switches into an Allosteric Agonist.

The WNT pathway interconnects a network of signaling events involved in a huge plethora of cellular processes, from organogenesis to tissue homeostasis. Despite its importance, the exiguity of organic drugs directly targeting the members of the Frizzled family of WNT receptors has hampered progress across the whole spectrum of biological fields in which the signaling is involved. We here present FzM1.8, a small molecule acting as an allosteric agonist of Frizzled receptor FZD4. FzM1.8 derives from FzM1, a negative allosteric modulator of the receptor. Replacement of FzM1 thiophene with a carboxylic moiety induces a molecular switch in the lead and transforms the molecule into an activator of WNT signaling. We here show that, in the absence of any WNT ligand, FzM1.8 binds to FZD4, promotes recruitment of heterotrimeric G proteins, and biases WNT signaling toward a noncanonical route that involves PI3K. Finally, in colon cancer cells, we prove that the FZD4/PI3K axis elicited by FzM1.8 preserves stemness and promotes proliferation of undifferentiated cells.

Incomplete Segregation of MSH6 Frameshift Variants with Phenotype of Lynch Syndrome.

Abstract: Lynch syndrome (LS), the most frequent form of hereditary colorectal cancer, involves mutations in mismatch repair genes. The aim of this study was to identify mutations in MSH6 from 97 subjects negative for mutations in MLH1 and MSH2. By direct sequencing, we identified 27 MSH6 variants, of which, nine were novel. To verify the pathogenicity of these novel variants, we performed in silico and segregation analyses. Three novel variants were predicted by in silico analysis as damaging mutations and segregated with the disease phenotype; while a novel frameshift deletion variant that was predicted to yield a premature stop codon did not segregate with the LS phenotype in three of four cases in the family. Interestingly, another frame-shift variant identified in this study, already described in the literature, also did not segregate with the LS phenotype in one of two affected subjects in the family. In all affected subjects of both families, no mutation was detected in other MMR genes. Therefore, it is expected that within these families, other genetic factors contribute to the disease either alone or in combination with MSH6 variants. We conclude that caution should be exercised in counseling for MSH6-associated LS family members.

Differential expression of PTEN gene correlates with phenotypic heterogeneity in three cases of patients showing clinical manifestations of PTEN hamartoma tumour syndrome.

Cowden syndrome (CS), Bannayan-Riley-Ruvalcaba syndrome (BRRS) and proteus syndrome are disorders known as PTEN hamartoma tumour syndrome (PHTS), that can show remarkable clinical overlap and are all caused by germline PTEN mutations. We here present two families, one affected by CS and the other affected by BRRS, both carriers of specific pathogenetic missense mutation in exon 5 of PTEN gene, within the catalitic domain. Both PHTS families exhibited extremely variable phenotypes, showing inter- and intra- familial variability. One of the two characterised mutations, the c.320A- > T; p.107Asp- > Val, identified in the CS family, was not previously described in the literature. Furthermore, the BRRS family, carrier of the c.406 T- > C; p.136Cys- > Arg mutation, shows a substantial alteration of PTEN protein expression that well correlates with intra-familial phenotypic variability. Finally, we describe an apparently sporadic case of an 80-year-old man, with a very low level of PTEN mRNA and protein expression, both in healthy and tumour colon mucosa, associated with a very atypical phenotype. He developed a metastatic colorectal carcinoma, macrocephaly and pheochromocytoma. According to literature data, our observations confirm that PTEN mutations of catalytic domain can cause different syndromes. We suggest that PTEN expression could represent one of the mechanisms involved in the remarkable heterogeneity of the clinical PHTS manifestations within affected families. Furthermore, constitutive strong decrease of PTEN expression in colon normal mucosa could be associated with late onset of colorectal cancer.

Co-Occurrence of Beckwith-Wiedemann Syndrome and Early-Onset Colorectal Cancer.

CRC is an adult-onset carcinoma representing the third most common cancer and the second leading cause of cancer-related deaths in the world. EO-CRC (<45 years of age) accounts for 5% of the CRC cases and is associated with cancer-predisposing genetic factors in half of them. Here, we describe the case of a woman affected by BWSp who developed EO-CRC at age 27. To look for a possible molecular link between BWSp and EO-CRC, we analysed her whole-genome genetic and epigenetic profiles in blood, and peri-neoplastic and neoplastic colon tissues. The results revealed a general instability of the tumor genome, including copy number and methylation changes affecting genes of the WNT signaling pathway, CRC biomarkers and imprinted loci. At the germline level, two missense mutations predicted to be likely pathogenic were found in compound heterozygosity affecting the Cystic Fibrosis (CF) gene CFTR that has been recently classified as a tumor suppressor gene, whose dysregulation represents a severe risk factor for developing CRC. We also detected constitutional loss of methylation of the KCNQ1OT1:TSS-DMR that leads to bi-allelic expression of the lncRNA KCNQ1OT1 and BWSp. Our results support the hypothesis that the inherited CFTR mutations, together with constitutional loss of methylation of the KCNQ1OT1:TSS-DMR, initiate the tumorigenesis process. Further somatic genetic and epigenetic changes enhancing the activation of the WNT/beta-catenin pathway likely contributed to increase the growth advantage of cancer cells. Although this study does not provide any conclusive cause-effect relationship between BWSp and CRC, it is tempting to speculate that the imprinting defect of BWSp might accelerate tumorigenesis in adult cancer in the presence of predisposing genetic variants.

Beta catenin and cytokine pathway dysregulation in patients with manifestations of the "PTEN hamartoma tumor syndrome".

BACKGROUND: The "PTEN hamartoma tumor syndrome" (PHTS) includes a group of syndromes caused by germline mutations within the tumor suppressor gene "phosphatase and tensin homolog deleted on chromosome ten" (PTEN), characterized by multiple polyps in the gastrointestinal tract and by a highly increased risk of developing malignant tumours in many tissues. The current work clarifies the molecular basis of PHTS in three unrelated Italian patients, and sheds light on molecular pathway disregulation constitutively associated to PTEN alteration. METHODS: We performed a combination of RT-PCR, PCR, sequencing of the amplified fragments, Real Time PCR and western blot techniques. RESULTS: Our data provide the first evidence of ß-catenin accumulation in blood cells of patients with hereditary cancer syndrome caused by germ-line PTEN alteration. In addition, for the first time we show, in all PHTS patients analysed, alterations in the expression of TNFα, its receptors and IL-10. Importantly, the isoform of TNFRI that lacks the DEATH domain (TNFRSF1ß) was found to be overexpressed. CONCLUSION: In light of our findings, we suggest that the PTEN pathway disregulation could determine, in non-neoplastic cells of PHTS patients, cell survival and pro-inflammatory stimulation, mediated by the expression of molecules such as ß-catenin, TNFα and TNFα receptors, which could predispose these patients to the development of multiple cancers.

A multicenter randomized phase 4 trial comparing sodium picosulphate plus magnesium citrate vs. polyethylene glycol plus ascorbic acid for bowel preparation before colonoscopy. The PRECOL trial.

Background: Adequate bowel preparation before colonoscopy is crucial. Unfortunately, 25% of colonoscopies have inadequate bowel cleansing. From a patient perspective, bowel preparation is the main obstacle to colonoscopy. Several low-volume bowel preparations have been formulated to provide more tolerable purgative solutions without loss of efficacy. Objectives: Investigate efficacy, safety, and tolerability of Sodium Picosulphate plus Magnesium Citrate (SPMC) vs. Polyethylene Glycol plus Ascorbic Acid (PEG-ASC) solutions in patients undergoing diagnostic colonoscopy. Materials and methods: In this phase 4, randomized, multicenter, two-arm trial, adult outpatients received either SPMC or PEG-ASC for bowel preparation before colonoscopy. The primary aims were quality of bowel cleansing (primary endpoint scored according to Boston Bowel Preparation Scale) and patient acceptance (measured with six visual analogue scales). The study was open for treatment assignment and blinded for primary endpoint assessment. This was done independently with videotaped colonoscopies reviewed by two endoscopists unaware of study arms. A sample size of 525 patients was calculated to recognize a difference of 10% in the proportion of successes between the arms with a two-sided alpha error of 0.05 and 90% statistical power. Results: Overall 550 subjects (279 assigned to PEG-ASC and 271 assigned to SPMC) represented the analysis population. There was no statistically significant difference in success rate according to BBPS: 94.4% with PEG-ASC and 95.7% with SPMC (P = 0.49). Acceptance and willing to repeat colonoscopy were significantly better for SPMC with all the scales. Compliance was less than full in 6.6 and 9.9% of cases with PEG-ASC and SPMC, respectively (P = 0.17). Nausea and meteorism were significantly more bothersome with PEG-ASC than SPMC. There were no serious adverse events in either group. Conclusion: SPMC and PEG-ASC are not different in terms of efficacy, but SPMC is better tolerated than PEG-ASC. SPMC could be an alternative to low-volume PEG based purgative solutions for bowel preparation. Clinical trial registration: [ClinicalTrials.gov], Identifier [NCT01649674 and EudraCT 2011-000587-10].

Reorganization of the endoscopic activity of Cancer Institutes during phase II of the Covid-19 emergency.

After the lockdown during the emergency phase of the Covid-19 pandemic, we have to deal with phase 2, a period of uncertain duration, with a controlled and progressive return to normalization, in which we need to reconcile our work and our movements with the presence of the virus on our territory. Digestive endoscopic activity is a high-risk transmission procedure for Covid-19. The measures put in place to protect healthcare personnel and patients are stressful and "time-consuming" and lead to a reduction in the number of endoscopic procedures that can be performed. In this scenario, the Oncological Institutes are forced to make a rigorous selection of patients to undergo endoscopic examinations and treatments, according to lists of exceptional priorities, in order to guarantee cancer patients and subjects at high risk of developing digestive tumors, a preferential diagnostic and therapeutic process, protected from contagion risks. For this purpose, cuts and postponing times of endoscopic performances are here proposed, which go beyond the guidelines of scientific societies and have little evidences in the literature. These changes should be applied limited to this exceptional period and in proportion to the capacity of each operating unit in order to meet the demands of the patients.

Wnt pathway, angiogenetic and hormonal markers in sporadic and familial adenomatous polyposis-associated juvenile nasopharyngeal angiofibromas (JNA).

Juvenile nasopharyngeal angiofibroma (JNA) is a rare, invasive, and locally destructive tumor of the nasopharynx. The Wnt pathway, angiogenetic and hormonal factors are involved in the pathophysiology of JNA; it can result in an extracolonic manifestation of familial adenomatous polyposis (FAP) or in a sporadic tumor. All patients who underwent resection of JNA between 1991 and 2006 at the University of Modena and Reggio Emilia were studied to identify immunohistochemical markers of associated FAP syndrome. Paraffin-embedded JNA samples were analyzed immunohistochemically for the expression of adenomatous polyposis coli (APC), beta-catenin, E-cadherin, androgen receptor, and vascular endothelial growth factors receptor (VEGFR2). In one out of the 4 (25%) young patients affected by JNA the diagnosis of FAP syndrome linked to APC mutation was made. All of the sporadic and familial JNA tumors showed nuclear staining of beta-catenin, whereas altered APC expression was seen only in FAP-associated JNA. All cases were stained with VEGFR2. A combined clinical, immunohistochemical, and biomolecular screening may be useful for the identification of FAP among patients with a diagnosis of JNA. The Wnt pathway can be involved in the JNA pathogenesis either by somatic mutations of beta-catenin or by germline APC mutations. As the VEGFR has an important impact on the pathogenesis of JNA, we suggest that a targeted therapy with monoclonal antibodies against VEGFR might lead to a specific chemoprevention and treatment of these tumors and their recurrences.

Characterization of novel, large duplications in the MSH2 gene of three unrelated Lynch syndrome patients.

Lynch syndrome (LS) is associated with germ-line mutations in the DNA mismatch repair (MMR) genes, mainly MLH1, MSH2, MSH6, and PMS2. Most of genetic variants in the MMR genes predisposing to LS are point mutations, small deletions and insertions but large genomic rearrangements in the MMR genes also predisposing to Lynch syndrome. In this study, we report a novel, large rearrangement of the MSH2 gene, manifested by a duplication spanning a 14,846-bps region from intron 7 through intron 9. The breakpoints of this rearrangement were characterized by sequencing. Further analysis of the breakpoints revealed that this rearrangement was a product of Alu-mediated recombination. Finally, this large duplication was identified in three unrelated patients. Breakpoint analysis revealed the same junction fragments of introns 7 and 8 in the three index cases, suggesting a recurrent duplication or, alternatively, identity of the respective alleles by descent.

Large polypoid perineurioma of the transverse colon without crypt serration (NPS).

Intestinal perineuriomas without crypt serration are mainly polypoid lesions characterized by a proliferation of stromal cells expressing perineurial markers. These lesions morphologically differ from those with serrated crypts because of the serrated/hyperplastic architecture in addition to the disorganization of the crypts. These tumors, despite both expression of perineurial cell markers (epithelial membrane antigen, claudin-1, GLUT-1, and collagen type IV), show well-characterized molecular differences such as BRAFV600E mutation, suggesting that they might represent two distinct variants of a single lesion. In this report, we describe a polypoid intestinal perineurioma without crypt serration of the transverse colon, showing an unusual large size compared with other reported polypoid lesions ranging from 0.2 to 0.6 cm in size.

WNT Inhibitory Activity of Malus Pumila miller cv Annurca and Malus domestica cv Limoncella Apple Extracts on Human Colon-Rectal Cells Carrying Familial Adenomatous Polyposis Mutations.

Inhibitors of the Wingless-related Integration site (WNT)/ß-catenin pathway have recently been under consideration as potential chemopreventive agents against Familial Adenomatous Polyposis (FAP). This autosomal-dominant syndrome is caused by germline mutations in the gene coding for the protein APC and leads to hyperactivation of the WNT/ß-catenin signaling pathway, uncontrolled intestinal cell proliferation and formation of adenocarcinomas. The aim of the present work was to: (i) test, on in vitro cultures of cells carrying FAP mutations and on ex vivo biopsies of FAP patients, the WNT inhibitory activity of extracts from two common southern Italian apples, Malus pumila Miller cv. 'Annurca' and Malus domestica cv 'Limoncella'; (ii) identify the mechanisms underpinning their activities and; (iii) evaluate their potency upon gastrointestinal digestion. We here show that both Annurca and Limoncella apple extracts act as WNT inhibitors, mostly thanks to their polyphenolic contents. They inhibit the pathway in colon cells carrying FAP mutations with active dilutions falling in ranges close to consumer-relevant concentrations. Food-grade manufacturing of apple extracts increases their WNT inhibitory activity as result of the conversion of quercetin glycosides into the aglycone quercetin, a potent WNT inhibitor absent in the fresh fruit extract. However, in vitro simulated gastrointestinal digestion severely affected WNT inhibitory activity of apple extracts, as result of a loss of polyphenols. In conclusion, our results show that apple extracts inhibit the WNT pathway in colon cells carrying FAP mutations and represent a potential nutraceutical alternative for the treatment of this pathology. Enteric coating is advisable to preserve the activity of the extracts in the colon-rectal section of the digestive tract.