Uncovering the potential for a weakly supervised end-to-end model in recognising speech from patient with post-stroke aphasia

Post-stroke speech and language deficits (aphasia) significantly impact patients' quality of life. Many with mild symptoms remain undiagnosed, and the majority do not receive the intensive doses of therapy recommended, due to healthcare costs and/or inadequate services. Automatic Speech Recognition (ASR) may help overcome these difficulties by improving diagnostic rates and providing feedback during tailored therapy. However, its performance is often unsatisfactory due to the high variability in speech errors and scarcity of training datasets. This study assessed the performance of Whisper, a recently released end-to-end model, in patients with post-stroke aphasia (PWA). We tuned its hyperparameters to achieve the lowest word error rate (WER) on aphasic speech. WER was significantly higher in PWA compared to age-matched controls (10.3% vs 38.5%, p < 0.001). We demonstrated that worse WER was related to the more severe aphasia as measured by expressive (overt naming, and spontaneous speech production) and receptive (written and spoken comprehension) language assessments. Stroke lesion size did not affect the performance of Whisper. Linear mixed models accounting for demographic factors, therapy duration, and time since stroke, confirmed worse Whisper performance with left hemispheric frontal lesions. We discuss the implications of these findings for how future ASR can be improved in PWA

Analysis of the Thymidylate Synthase Gene Structure in Colorectal Cancer Patients and Its Possible Relation with the 5-Fluorouracil Drug Response

Thymidylate synthase (TS) catalyzes methylation of dUMP to dTMP and it is the target for the 5-Fluorouracil (5-FU) activity. Barbour et al. showed that variant structural forms of TS in tumour cell lines confer resistance to fluoropyrimidines. We planned to perform the whole TS gene structure by means of sequencing techniques in human colorectal cancer (CRC) samples to try to identify the presence of any possible TS variant form that could be responsible of fluoropyrimidines drug resistance and of the worse prognosis. We performed the TS-DNA gene sequence in 68 CRC from patients of A, B, and C Dukes' stages and different histological grade, but we did not find any mutation in the TS-DNA structure. In the future we intend to widen the TS structure analysis to the metastatic CRCs, because due to their higher genomic instability, they could present a TS variant form responsible of the fluoropyrimidines drug resistance and the worse prognosis

Thymidylate synthase gene promoter polymorphisms are associated with TSmRNA expressions but not with microsatellite instability in colorectal cancer

Abstract BACKGROUND: Microsatellite instability (MSI) is a biological characteristic of most tumours, being involved in 85% of hereditary non-polyposis colorectal cancer (HNPCC). It also occurs in 10-15% of sporadic colorectal cancers (CRC). HNPCC appears to be caused by germline mutations in mismatch repair (MMR) genes, which are responsible for repairing single base-pair mismatches. MSI is also associated with a better response of CRC to adjuvant chemotherapy with fluoropyrimidines. We investigated any relationship between the MSI status and the TSmRNA expression, the polymorphisms of 5-Fluorouracil (5-FU cellular target, the enzyme thymidylate synthase (TS) and TS expression evaluated by means of immunohistochemistry. MATERIALS AND METHODS: A series of 80 colorectal cancers was evaluated for MSI and polymorphisms in the 3'UTR and the 5'UTR of the TS gene by a PCR assay. TSmRNA was quantified by real-time PCR and the TS expression by immunohistochemical assay. RESULTS: There was no significant association between the polymorphisms in the TS gene and the MSI or between the TSmRNA expression and the MSI status. CRC with a 3R/3R or 2R/3R genotype showed a significantly higher TSmRNA expression than those with the 2R/2R genotype (p = 0.001 and p = 0.028, respectively). Another significant association was found between the TSmRNA expression and the TS immunohistochemical determination (p = < 0.05). No association was found between the polymorphism of the 3'UTR and the TSmRNA expression. CONCLUSION: Our data show that there is no association between MSI status and the polymorphisms in the 3' and 5' UTRs and the TS expression. Tumour samples displaying the 3R/3R or 2R/3R genotype of TS have higher TSmRNA levels than the 2R/2R genotype. Polymorphic variant of the 3'UTR does not influence the TSmRNA level. We found a relationship between the TSmRNA expression, evaluated by real-time PCR, and with the TS level determined by immunohistochemical assay. Thus, genotyping of the 5'UTR and quantification of the TSmRNA expression in human CRC could be considered as predictors for response to SFU-based chemotherapy. The evaluation of the TS expression by means of immunohistochemistry assay remains a safe and reliable assay in CRC

Effects of Ti6Al4V mechanical and thermal surface modification on the adhesion of a chitosan-bioactive glass coating

Biomedical implants interact with human tissues introducing significant perturbation into the body. Implant surfaces can be then functionalized enabling better biocompatibility. At the same time, the additional use of a coating provides further functions such as corrosion protection, osteointegration, and drug delivery. In this context, a composite made of chitosan and bioactive glass nanoparticles has been used for coating Ti6Al4V alloy samples processed beforehand using different processes, i.e., polishing, milling, grit blasting, and electrical discharge machining. Experiments have been carried out to correlate substrate surface conditions and coating effectiveness in terms of scratch resistance with the final aim to obtain suitable guidelines to improve substrate-coating performances

Clinical relevance of thymidylate syntetase expression in the signet ring cell histotype component of colorectal carcinoma

Thymidylate Synthase (TS) is the key enzyme for DNA synthesis pathways and is inhibited by 5-fluorouracil (5FU). The aim of this work was to study TS expression and the proliferation rate in the different histological types of colorectal carcinoma (CRC). 50 patients with CRC were included in this study and evaluated immunohistochemically using the monoclonal antibodies, TS106 and Ki67. 20 tumours were of the intestinal type, 15 cases were signet ring cell carcinoma (SRCCs) and 15 cases were "mixed-type", with at least two different histological components. Intestinal and mucinous histotypes were positive for TS and Ki67, while "signet ring cell" samples were negative or showed only weak and focal positivity for both the TS and Ki67 antibodies. Our results show that signet ring cells (that are also often present in intestinal and mucinous carcinomas), are in the post-mitotic phase of the cell cycle and show a low proliferation index and TS expression. As TS is the key enzyme for DNA synthesis pathways and is inhibited by 5-fluorouracil (5FU), we can hypothesise that TS expression levels in the different histotypes of CRC could affect the potential responsiveness of these tumours to fluoropyrimidine chemotherapy, with a low efficacy being expected in signet ring cell areas

A Troubling Diagnosis of Verrucous Squamous Cell Carcinoma (“the Bad Kind” of Keratosis) and the Need of Clinical and Pathological Correlations: A Review of the Literature with a Case Report

Verrucous carcinoma (also known as Ackerman tumor) is an uncommon exophytic low-grade well-differentiated variant of squamous cell carcinoma. This neoplasm typically involves the oral cavity, larynx, genitalia, skin, and esophagus. It is well known for its locally aggressiveness and for its clinically slow-growing behaviour with minimal metastatic potential. Verrucous carcinoma of oral cavity is so closely aligned with the use of snuff and chewing tobacco that it has been called the “snuff dipper's cancer”. Recent studies have proved the role of HPV. The typical clinical presentation of oral verrucous carcinoma has long been known, as its remarkably innocuous appearance and biological behaviour. In this work, we report a review of the scientific literature and describe a troublesome case of oral verrucous cancer

Bioptic prostatic inflammation correlates with false positive rates of multiparametric magnetic resonance imaging in detecting clinically significant prostate cancer

ntroduction: The aim of this article was to determine the impact of bioptic prostatic inflammation (PI) on the false positive rate of multiparametric magnetic resonance imaging (mp-MRI) in detecting clinically significant prostate ancer (csPCa). Material and methods: Our prostate biopsy database was queried to identify patients who underwent mp-MRI before PB at our institution. A dedicated uropathologist prospectively assessed bioptic PI using the Irani scores. We evaluated the association between mp-MRI findings, bioptic Gleason grade (GG) and aggressiveness of PI, and PCa detection. Results: In total, 366 men were included. In patients with Prostate Imaging Reporting and Data System (PIRADS) 4-5 lesions, the csPCa (GG ≥2) rate was significantly higher in those with low-grade than in those with high-grade PI (36% vs 29.7%; p = 0.002), and in those with low-aggressive than in those with high-aggressive PI (37.7% vs 30.1%; p = 0.0003). The false positive rates of PIRADS 4-5 lesions for any PCa were 34.2% and 57.8% for low- and high-grade PI, respectively (p = 0.002); similarly, they were 29.5% and 59.4% for mildly and highly-aggressive PI (p = 0.0003). Potential study limitations include its retrospective analysis and single-center study and lack of assessment of the type of PI. Conclusions: Bioptic PI directly correlates with false positive rates of mp-MRI in detecting csPCa. Clinicians should be aware that PI remains the most common pitfall of mp-MRI

Prostate cancer biomarkers: a practical review based on different clinical scenarios

Traditionally, diagnosis and staging of prostate cancer (PCa) have been based on prostate-specific antigen (PSA) level, digital rectal examination (DRE), and transrectal ultrasound (TRUS) guided prostate biopsy. Biomarkers have been introduced into clinical practice to reduce the overdiagnosis and overtreatment of low-grade PCa and increase the success of personalized therapies for high-grade and high-stage PCa. The purpose of this review was to describe available PCa biomarkers and examine their use in clinical practice. A nonsystematic literature review was performed using PubMed and Scopus to retrieve papers related to PCa biomarkers. In addition, we manually searched websites of major urological associations for PCa guidelines to evaluate available evidence and recommendations on the role of biomarkers and their potential contribution to PCa decision-making. In addition to PSA and its derivates, thirteen blood, urine, and tissue biomarkers are mentioned in various PCa guidelines. Retrospective studies have shown their utility in three main clinical scenarios: (1) deciding whether to perform a biopsy, (2) distinguishing patients who require active treatment from those who can benefit from active surveillance, and (3) defining a subset of high-risk PCa patients who can benefit from additional therapies after RP. Several validated PCa biomarkers have become commercially available in recent years. Guidelines now recommend offering these tests in situations in which the assay result, when considered in combination with routine clinical factors, is likely to affect management. However, the lack of direct comparisons and the unproven benefits, in terms of long-term survival and cost-effectiveness, prevent these biomarkers from being integrated into routine clinical use

The effect of CYP3A5 and ABCB1 single nucleotide polymorphisms on tacrolimus dose requirements in Caucasian liver transplant patients

Background: Tacrolimus is a substrate of cytochrome P-450 (CYP) 3A enzyme and of the drug transporter ABCBl. We have investigated the effects of possible relevant CYP3A5 and ABCBl single nucleotide polymorphisms (SNPs) present in both donors and recipients on tacrolimus blood levels achieved in a population of 32 Caucasian liver transplant patients. Material/Methods: At 1, 3 and 6 months after transplantation, tacrolimus doses (mg/kg/day) and trough blood levels (C0) were determined. Polymerase chain reaction followed by restriction fragment length polymorphism analysis was used for gen-otyping CYP3A5*3 [6986A&gt;G] as well as ABCBl at exons 21 [2677G&gt;T] and 26 [3435C&gt;T]. Results:87.5% of the population showed a CYP3A5*3/*3 genotype. For the ABCBl SNPs, in the case of 3435C&gt;T the total frequency observed for the allelic variant was 50%. For the 2677G&gt;T, the total frequency of the allelic variant was 12.5%, lower than in other Caucasian populations and without any significant linkage with 3435C&gt;T. At 3 and 6 months after transplantation, tacrolimus dose requirements were significantly higher in patients receiving a liver with one copy of the *1 al-lele compared to those homozygous for the *3 allele (0.111±0.057 vs. 0.057±0.030 [P&lt;0.05] at 3 month and 0.086±0.051 vs. 0.044±0.025 [P&lt;0.05] at 6 month). For the recipients' genotypes, the presence of at least one *1 copy tended, though not statistically significantly, to increase tacrolimus doses. With regard to the ABCBl SNPs, they did not show any influence on tacrolimus dosing requirements. Conclusions: Pharmacogenetic analysis of CYP3A5 in the donor could contribute to determine the appropriate initial dosage of tacrolimus in liver transplant patient

Metabolomic profile of glycolysis and the pentose phosphate pathway identifies the central role of glucose-6-phosphate dehydrogenase in clear cell-renal cell carcinoma.

The analysis of cancer metabolome has shown that proliferating tumor cells require a large quantities of different nutrients in order to support their high rate of proliferation. In this study we analyzed the metabolic profile of glycolysis and the pentose phosphate pathway (PPP) in human clear cell-renal cell carcinoma (ccRCC) and evaluate the role of these pathways in sustaining cell proliferation, maintenance of NADPH levels, and production of reactive oxygen species (ROS). Metabolomic analysis showed a clear signature of increased glucose uptake and utilization in ccRCC tumor samples. Elevated levels of glucose-6-phosphate dehydrogenase (G6PDH) in association with higher levels of PPP-derived metabolites, suggested a prominent role of this pathway in RCC-associated metabolic alterations. G6PDH inhibition, caused a significant decrease in cancer cell survival, a decrease in NADPH levels, and an increased production of ROS, suggesting that the PPP plays an important role in the regulation of ccRCC redox homeostasis. Patients with high levels of glycolytic enzymes had reduced progression-free and cancer-specific survivals as compared to subjects with low levels. Our data suggest that oncogenic signaling pathways may promote ccRCC through rerouting the sugar metabolism. Blocking the flux through this pathway may serve as a novel therapeutic target