Subclinical finding in the perception of tactile sensation involvement after SARS-CoV2 infection: comparison with healthy controls using Semmes–Weinstein monofilament testing

BackgroundPost-acute COVID-19 syndrome patients complain of sensory alterations, mainly positive symptoms such as paresthesia or neuropathic pain but also decreased tactile sensation. Using the Semmes–Weinstein monofilament test (SWMT), our study aims to confront recently infected SARS-CoV2 subjects with a control group.MethodsThis is a cross-sectional, single-centric study. We performed the SWMT (North Coast Medical Inc.) on 30 patients with previous SARS-CoV2 infection (COVID group) and 46 controls (control group). These patients did not present comorbidities or sensory impairment and did not take any medications. The control group tested negative for SARS-CoV2 infection since the COVID-19 pandemic; the COVID group was examined for this study after the resolution of the infection. We tested the threshold of tactile sensation of the tips of the thumb, index, and little finger of each hand, one hand at a time; the dorsum and the hypothenar regions were also tested.ResultsBoth groups presented the perception of tactile sensation within the reference value. Despite this result, subclinical changes suggestive of the involvement in peripheral sensory nerve function have been identified in the tested sites in the COVID group compared to the control group. The overall mean target force (grams) was higher in the COVID group than in the control group: 27 (7) vs. 19 (10) mg, p < 0.001.ConclusionControls and the COVID group infection had normal tactile sensation thresholds. However, the COVID group presented a higher threshold than the control group, suggesting a possible subclinical perception of tactile sensation involvement of A-beta nerve fibers

p27kip1 expression and phosphorylation dictate Palbociclib sensitivity in KRAS-mutated colorectal cancer

Abstract In colorectal cancer, mutation of KRAS (RASMUT) reduces therapeutic options, negatively affecting prognosis of the patients. In this setting, administration of CDK4/6-inhibitors, alone or in combination with other drugs, is being tested as promising therapeutic strategy. Identifying sensitive patients and overcoming intrinsic and acquired resistance to CDK4/6 inhibition represent still open challenges, to obtain better clinical responses. Here, we investigated the role of the CDK inhibitor p27kip1 in the response to the selective CDK4/6-inhibitor Palbociclib, in colorectal cancer. Our results show that p27kip1 expression inversely correlated with Palbociclib response, both in vitro and in vivo. Generating a model of Palbociclib-resistant RASMUT colorectal cancer cells, we observed an increased expression of p27kip1, cyclin D, CDK4 and CDK6, coupled with an increased association between p27kip1 and CDK4. Furthermore, Palbociclib-resistant cells showed increased Src-mediated phosphorylation of p27kip1 on tyrosine residues and low doses of Src inhibitors re-sensitized resistant cells to Palbociclib. Since p27kip1 showed variable expression in RASMUT colorectal cancer samples, our study supports the possibility that p27kip1 could serve as biomarker to stratify patients who might benefit from CDK4/6 inhibition, alone or in combination with Src inhibitors

CDKN1B mutation and copy number variation are associated with tumor aggressiveness in luminal breast cancer

The CDKN1B gene, encoding for the CDK inhibitor p27kip1 , is mutated in defined human cancer subtypes, including breast, prostate carcinomas and small intestine neuroendocrine tumors (SI-NET). Lessons learned from SI-NET suggests that CDKN1B mutations could be subclonal, raising the question of whether a deeper sequencing approach could lead to the identification of higher numbers of patients with mutations. Here, we addressed this question and analyzed human cancer biopsies from breast (n=396), ovarian (n=110) and head and neck squamous carcinomas (n=202) patients, using an ultra-deep sequencing approach. Notwithstanding this effort, the mutation rate of CDKN1B remained substantially aligned with values from the literature, showing that essentially only hormone-receptor positive breast cancer (HR+, luminal BC) displayed CDKN1B mutations in a relevant number of cases (3%). However, the analysis of copy number variation showed that another fraction of luminal BC displayed loss (8%) or gain (6%) of the CDKN1B gene, further reinforcing the idea that the function of p27kip1 is important in this type of tumor. Intriguingly, an enrichment for CDKN1B alterations was found in samples from pre-menopausal luminal BC patients (n=227, 4%) and in circulating cell-free DNA from metastatic luminal BC patients (n=59, 8.5%), suggesting that CDKN1B alterations could correlate with tumor aggressiveness and/or occur later during disease progression. Notably, many of the identified somatic mutations resulted in p27kip1 protein truncation leading to loss of most of the protein or of its C-terminal domain. Using a gene editing approach in a luminal BC cell line, MCF-7, we observed that the expression of p27kip1 truncating mutants that lose the C-terminal domains failed to rescue most of the phenotypes induced by CDKN1B gene knock-out, indicating that the functions retained by the C-terminal portion are critical for its role as oncosuppressor, at least in luminal BC. This article is protected by copyright. All rights reserved

MAVIS: preliminary design of the adaptive optics module

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