Incidence of Disease Recurrence in Patients With Colon and Upper Rectum Adenocarcinoma Stage II and III Receiving Adjuvant Capecitabine Monotherapy: Do Number of Chemotherapy Cycles and Relative Dose Intensity of the Drug Play a Role?

INTRODUCTION/BACKGROUND: Adjuvant capecitabine monotherapy is an option for colon and upper rectum adenocarcinoma patients, providing they have stage II disease with an intermediate risk of recurrence, or stage III but they are above 70's or they have comorbidities. We wanted to examine whether the number of chemotherapy cycles and the relative dose intensity (RDI) of capecitabine monotherapy in the adjuvant setting are affecting disease recurrence. PATIENTS AND METHODS: We included patients with completely resected stage II and III colon and upper rectum cancer who received adjuvant capecitabine monotherapy, from 2003 until May 2020. Patients with early relapse, i.e. during chemotherapy or within 6 months after the completion of adjuvant chemotherapy, and those with rectal cancer who received radiotherapy were excluded. Patients were divided into 3 groups based on the number of chemotherapy cycles received and the RDI. Group A included patients with ≤4 cycles of chemotherapy, group B patients with >4 cycles of chemotherapy and RDI ≤80%, and group C patients with >4 cycles of chemotherapy and RDI >80%. Study's endpoint, was recurrence free survival (RFS). RESULTS: Two hundred twenty six patients with stage II and III disease (164 and 62 respectively) were included. Sixteen, 166 and 44 were included in groups A, B and C respectively. After a median follow-up of 41 months, 21 patients (9,3%) had relapsed. Patients belonging to group C were found to have a trend for lower relapse rate compared to patients belonging to group A or group B. CONCLUSION: Number of adjuvant capecitabine cycles and RDI might play a role in RFS in patients with stage II and III colon and upper rectum adenocarcinoma.

COVID-19 Phenotypes and Comorbidity: A Data-Driven, Pattern Recognition Approach Using National Representative Data from the United States.

The aim of our study was to determine COVID-19 syndromic phenotypes in a data-driven manner using the survey results based on survey results from Carnegie Mellon University's Delphi Group. Monthly survey results (>1 million responders per month; 320,326 responders with a certain COVID-19 test status and disease duration <30 days were included in this study) were used sequentially in identifying and validating COVID-19 syndromic phenotypes. Logistic Regression-weighted multiple correspondence analysis (LRW-MCA) was used as a preprocessing procedure, in order to weigh and transform symptoms recorded by the survey to eigenspace coordinates, capturing a total variance of >75%. These scores, along with symptom duration, were subsequently used by the Two Step Clustering algorithm to produce symptom clusters. Post-hoc logistic regression models adjusting for age, gender, and comorbidities and confirmatory linear principal components analyses were used to further explore the data. Model creation, based on August's 66,165 included responders, was subsequently validated in data from March−December 2020. Five validated COVID-19 syndromes were identified in August: 1. Afebrile (0%), Non-Coughing (0%), Oligosymptomatic (ANCOS); 2. Febrile (100%) Multisymptomatic (FMS); 3. Afebrile (0%) Coughing (100%) Oligosymptomatic (ACOS); 4. Oligosymptomatic with additional self-described symptoms (100%; OSDS); 5. Olfaction/Gustatory Impairment Predominant (100%; OGIP). Our findings indicate that the COVID-19 spectrum may be undetectable when applying current disease definitions focusing on respiratory symptoms alone.

Outside-in induction of the IFITM3 trafficking system by infections, including SARS-CoV-2, in the pathobiology of Alzheimer's disease.

BACKGROUND: IFITM3 is a viral restriction protein that enables sequestration of viral particles and subsequent trafficking to lysosomes. Recently, IFITM3 upregulation was found to induce gamma - secretase activity and the production of amyloid beta. The purpose of this study was to determine whether dysregulation of IFITM3-dependent pathways was present in neurons and peripheral immune cells donated by AD patients. As a secondary aim, we sought to determine whether these perturbations could be induced by viruses, including SARS-CoV-2. METHODS: Gene set enrichment analyses (GSEA) previously performed on publicly available transcriptomic data from tissues donated by AD patients were screened for enriched pathways containing IFITM3. Subsequently, signature containing IFITM3, derived from entorhinal cortex (EC) neurons containing neurofibrillary tangles (NFT) was screened for overlap with curated, publicly available, viral infection-induced gene signatures (including SARS-CoV-2). RESULTS: GSEA determined that IFITM3 gene networks are significantly enriched both in CNS sites (entorhinal and hippocampal cortices) and in peripheral blood mononuclear cells (PBMCs) donated by AD patients. Overlap screening revealed that IFITM3 signatures are induced by several viruses, including SARS-CoV, MERS-CoV, SARS-CoV-2 and HIV-1 (adjusted p-value <0.001; Enrichr Database). DISCUSSION: A data-driven analysis of AD tissues revealed IFITM3 gene signatures both in the CNS and in peripheral immune cells. GSEA revealed that an IFITM3 derived gene signature extracted from EC/NFT neurons overlapped with those extracted from publicly available viral infection datasets, including SARS-CoV-2. Our results are in line with currently emerging evidence on IFITM3's role in AD, and SARS-CoV-2's potential contribution in the setting of an expanded antimicrobial protection hypothesis.

Epigenetic regulation of apoptosis via the PARK7 interactome in peripheral blood mononuclear cells donated by tuberculosis patients vs. healthy controls and the response to treatment: A systems biology approach.

AIMS: The aims of our study were to determine for the first time differentially expressed genes (DEGs) and enriched molecular pathways involving the PARK7 interactome in PBMCs donated from tuberculosis patients. METHODS: Data on a previously reconstructed PARK7 interactome (Vavougios et al., 2017) from datasets GDS4966 (Case-Control) and GDS4781 (Treatment Series) were retrieved from the Gene Expression Omnibus (GEO) repository. Gene Enrichment analysis was performed via the STRING algorithm and the GeneTrail2 software. RESULTS: 17 and 22 PARK7 interactores were determined as DEGs in the active TB vs HD and Treatment Series subset analyses, correspondingly, associated with significantly enriched pathways (FDR <0.05) involving p53 and PTEN mediated, stress responsive apoptosis regulation pathways. The treatment subset was characterized by the emergence of an additional layer of transcriptional regulation mediated by polycomb proteins among others, as well as TLR-mediated and cytokine survival signaling. Finally, the enrichment of a Parkinson's disease signature including PARK7 interactors was determined by its differential regulation both in the exploratory analyses (FDR = 0.024), as well as the confirmatory analyses (FDR = 1.81e-243). CONCLUSIONS: Our in silico analysis revealed for the first time the role of PARK7's interactome in regulating the epigenetics of the PBMC lifecycle and Mtb symbiosis.

Participatory modelling for poverty alleviation using fuzzy cognitive maps and OWA learning aggregation.

Participatory modelling is an emerging approach in the decision-making process through which stakeholders contribute to the representation of the perceived causal linkages of a complex system. The use of fuzzy cognitive maps (FCMs) for participatory modelling helps policy-makers develop dynamic quantitative models for strategising development interventions. The aggregation of knowledge from multiple stakeholders provides consolidated and more reliable results. Average aggregation is the most common aggregation method used in FCMs-based modelling for weighted interconnections between concepts. This paper proposes a new aggregation method using learning OWA (ordered weighted averaging) operators for aggregating FCM weights assigned by various stakeholders. Besides, we report a comparative analysis of 'OWA learning aggregation' with the conventional average aggregation method, while evaluating the theory of change for the world's most extensive poverty alleviation programme in India. The results of the FCMWizard web-based tool show that the proposed method provides an opportunity to policy-makers for evaluating outcomes of proposed policies while addressing social resilience and economic mobility.

Double hit viral parasitism, polymicrobial CNS residency and perturbed proteostasis in Alzheimer's disease: A data driven, in silico analysis of gene expression data.

The aim of this study was to determine the interaction of peripheral immunity vs. the CNS in the setting of AD pathogenesis at the transcriptomic level in a data driven manner. For this purpose, publicly available gene expression data from the GEO Datasets repository. We performed differential gene expression and functional enrichment analyses were performed on the five retrieved studies: (a) three hippocampal cortex (HC) studies (b) one study of peripheral blood mononuclear cells (PBMC) and (c) one involving neurofibrillary tangle - containing neurons of the entorhinal cortex (NFT EC). Subsequently, BLAST was used to determine protein conservation between human proteins vs. microbial, whereas putative protein / oligopeptide antigenicity were determined via RANKPep. Gene ontology and pathway analyses revealed significantly enriched viral parasitism pathways in both PBMC and NFT - EC datasets, mediated by ribosomal protein families and epigenetic regulators. Among these, a salient viral pathway referred to Influenza A infection. NFT - EC annotations included leukocyte chemotaxis and immune response pathways. All datasets were significantly enriched for infectious pathways, as well as pathways involved in impaired proteostasis and non - phagocytic cell phagosomal cascades. In conclusion, our in silico analysis outlined an ad hoc model of AD pathophysiology in which double hit (PBMC and NFT-EC) viral parasitism is mediated by eukaryotic translational hijacking, and may be further implicated by impaired immune responses. Overall, our results overlap with the antimicrobial protection hypothesis of AD pathogenesis and support the notion of a pathogen - driven etiology.

Differences in dyslexic students before and after a remediation program: A clinical neuropsychological and event related potential study.

Developmental dyslexia is defined as an unexpected specific and persistent failure to acquire efficient reading skills despite conventional instruction, adequate intelligence and sociocultural opportunity. This article reports the outcomes of a study that evaluated the implementation of a 4-month intervention program. The intervention consisted of structured activities aiming at improving (a) the children's phonological awareness, (b) their visual and auditory memory, (c) their visual discrimination ability, and (d) their text comprehension. Participants were 12 children diagnosed as dyslexic matched with 12 typically achieving peers of similar age and gender. Baseline assessment consisted of a clinical neuropsychological battery of tests and Event Related Potentials (ERPs) and resulted in confirming the discrepancy between the dyslexic and the control group. Following the remediation program, the dyslexic group did not differ significantly from their control group in six out of eight neuropsychological tests. The electrophysiological results revealed that the two groups had similar P300 latencies in 12 out of the 15 electroencephalographic sites assessed. These findings suggest that children with dyslexia can improve their abilities through a remediation program which aims to strengthen their audio-visual and phonological processes along with their working memory capability.

Effective use of levosimendan in anthracycline-induced cardiomyopathy: A case report.

BACKGROUND: Anthracycline-induced cardiomyopathy is a serious side effect that ranges from mild left ventricular systolic impairment to congestive heart failure and cardiogenic shock. Currently, there is no evidence indicating the effective use of levosimendan in these cases. OBJECTIVE: We aim to present a case of life-threatening doxorubicin-induced cardiomyopathy that was successfully managed with levosimendan. CASE: A 48-year-old female with formerly normal heart function, who had been treated with doxorubicin-based regimens for dedifferentiated chondrosarcoma, presented with cardiomyopathy with low left ventricular ejection fraction eight months after the last infusion. As treatment with ramipril, carvedilol, and furosemide followed by dopamine and noradrenaline was not sufficient, levosimendan was administered. Left ventricular ejection fraction increased from 15% to 45% and her clinical condition improved. DISCUSSION: Although anthracycline-induced cardiomyopathy may have a poor prognosis, levosimendan was shown to be effective in this patient. Therefore, levosimendan may represent a possible therapeutic option in such cases.

Impact of Dose Reductions, Delays Between Chemotherapy Cycles, and/or Shorter Courses of Adjuvant Chemotherapy in Stage II and III Colorectal Cancer Patients: a Single-Center Retrospective Study.

PURPOSE: Most stage II or III colorectal cancer patients are receiving nowadays a 4 to 6-month course of adjuvant chemotherapy. However, delays between cycles, reductions in the doses of chemotherapy drugs, or even permanent omissions of chemotherapy cycles might take place due to side effects or patient's preference. We examined the impact of these treatment modifications on recurrence-free survival (RFS) and overall survival (OS). METHODS: We retrospectively collected data from colorectal cancer patients who had received adjuvant chemotherapy in our Department. Patients were categorized in five groups based on whether they had or not delays between chemotherapy cycles, dose reductions, and permanent omissions of chemotherapy cycles. Three-year RFS and OS of the five different groups were compared using the log-rank test and the Sidak approach. RESULTS: Five hundred and eight patients received treatment. Twenty seven percent of the patients had the full course of chemotherapy; the others had delays, dose reductions, or early termination of the treatment. No statistically significant differences were observed in 3-year RFS and OS between the five groups. A trend for worse RFS was noticed with early termination of treatment. A similar trend was also noticed for OS but only for stage II patients. CONCLUSION: In colorectal cancer patients, receiving adjuvant chemotherapy, delays between chemotherapy cycles, dose reductions of chemotherapy drugs, or even early termination of the treatment course do not seem to have a negative impact in 3-year RFS and OS; however, due to the trend of worse RFS in patients receiving shorter courses of chemotherapy, further studies are needed.