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Abstract The rechallenge strategy is based on the concept that a subset of patients with RAS wild‐type (WT) metastatic colorectal cancer (mCRC) could still benefit of epidermal growth factor receptor (EGFR) inhibition, after progression to an anti‐EGFR based‐therapy. We performed a pooled analysis of two‐phase II prospective trials to determine the role of rechallenge in third‐line mCRC patients with RAS/BRAF WT baseline circulating tumor DNA (ctDNA). Individual data of 33 and 13 patients from CAVE and CRICKET trials that received as third‐line therapy cetuximab rechallenge were collected. Overall survival (OS), Progression‐free survival (PFS), Overall response rate (ORR), Stable disease (SD) >6 months were calculated. Adverse events were reported. For the whole 46 patient population, median PFS (mPFS) was 3.9 months (95% Confidence Interval, CI 3.0–4.9) with median OS (mOS) of 16.9 months (95% CI 11.7–22.1). For CRICKET patients, mPFS was 3.9 months (95% CI 1.7–6.2); mOS was 13.1 months (95% CI 7.3–18.9) with OS rates at 12, 18, and 24 months of 62%, 23%, and 0%, respectively. For CAVE patients, mPFS was 4.1 months (95% CI 3.0–5.2); mOS was 18.6 months (95% CI 11.7–25.4) with OS rates at 12, 18, 24 months of 61%, 52%, 21%, respectively. Skin rash was more frequently reported in CAVE trial (87.9% vs. 30.8%; p = 0.001), whereas a increased incidence of hematological toxicities was observed in CRICKET trial (53.8%% vs. 12.1%; p = 0.003). Third‐line cetuximab rechallenge in combination with either irinotecan or avelumab in RAS/BRAF WT ctDNA mCRC patients represents a promising therapy.

BackgroundBiventricular failure is associated with high in‐hospital mortality. Limited data regarding the efficacy of biventricular Impella axial flow catheters (BiPella) support for biventricular failure exist. The aim of this study was to explore the clinical utility of percutaneously delivered BiPella as a novel acute mechanical support strategy for patients with cardiogenic shock complicated by biventricular failure. Methods and ResultsWe retrospectively analyzed data from 20 patients receiving BiPella for biventricular failure from 5 tertiary‐care hospitals in the United States. Left ventricular support was achieved with an Impella 5.0 (n=8), Impella CP (n=11), or Impella 2.5 (n=1). All patients received the Impella RP for right ventricular (RV) support. BiPella use was recorded in the setting of acute myocardial infarction (n=11), advanced heart failure (n=7), and myocarditis (n=2). Mean flows achieved were 3.4±1.2 and 3.5±0.5 for left ventricular and RV devices, respectively. Total in‐hospital mortality was 50%. No intraprocedural mortality was observed. Major complications included limb ischemia (n=1), hemolysis (n=6), and Thrombolysis in Myocardial Infarction major bleeding (n=7). Compared with nonsurvivors, survivors were younger, had a lower number of inotropes or vasopressors used before BiPella, and were more likely to have both devices implanted simultaneously during the same procedure. Compared with nonsurvivors, survivors had lower pulmonary artery pressures and RV stroke work index before BiPella. Indices of RV afterload were quantified for 14 subjects. Among these patients, nonsurvivors had higher pulmonary vascular resistance (6.8; 95% confidence interval [95% CI], 5.5–8.1 versus 1.9; 95% CI, 0.8–3.0; P

Leukodystrophies are a class of rare heterogeneous disorders which affect the white matter of the brain, ultimately leading to a disruption in brain development and a damaging effect on cognitive, motor and social-communicative development. These disorders present a great clinical heterogeneity, along with a phenotypic overlap and this could be partially due to contributions from environmental stimuli. It is in this context that there is a great need to investigate what other factors may contribute to both disease insurgence and phenotypical heterogeneity, and novel evidence are raising the attention toward the study of epigenetics and transcription mechanisms that can influence the disease phenotype beyond genetics. Modulation in the epigenetics machinery including histone modifications, DNA methylation and non-coding RNAs dysregulation, could be crucial players in the development of these disorders, and moreover an aberrant RNA maturation process has been linked to leukodystrophies. Here, we provide an overview of these mechanisms hoping to supply a closer step toward the analysis of leukodystrophies not only as genetically determined but also with an added level of complexity where epigenetic dysregulation is of key relevance. This article is categorized under: Regulatory RNAs/RNAi/Riboswitches > Regulatory RNA RNA in Disease and Development > RNA in Disease RNA in Disease and Development > RNA in Development., (© 2024 The Author(s). WIREs RNA published by Wiley Periodicals LLC.)

In this study, we exploit a recently developed fragment diabatization-based excitonic model, FrDEx, to simulate the electronic circular dichroism (ECD) spectra of three guanine-rich DNA sequences arranged in guanine quadruple helices with different topologies: thrombin binding aptamer (antiparallel), c-Myc promoter (parallel), and human telomeric sequence (3+1 hybrid). Starting from time-dependent density functional theory (TD-DFT) calculations with the M052X functional, we apply our protocol to parameterize the FrDEX Hamiltonian, which accounts for electron density overlap and includes both the coupling with charge transfer transitions and the effect of the surrounding bases on the local excitation of each chromophore. The TD-DFT/M052X spectral shapes are in good agreement with the experimental ones, the main source of discrepancy being related to the intrinsic error on the computed transition energies of guanine monomer. FrDEx spectra are fairly close to the reference TD-DFT ones, allowing a significant advance with respect to a more standard excitonic Hamiltonian. We also show that the ECD spectra are sensitive to the inclusion of the inner K + cation in the calculation., (© 2023 The Authors. Chirality published by Wiley Periodicals LLC.)

Background: Coronavirus disease 2019 (COVID-19) is a recently recognized viral infective disease which can be complicated by acute respiratory stress syndrome (ARDS) and cardiovascular complications including severe arrhythmias, acute coronary syndromes, myocarditis and pulmonary embolism. The aim of the present study was to identify the clinical conditions and echocardiographic parameters associated with in-hospital mortality in COVID-19., Methods: This is a multicentre retrospective observational study including seven Italian centres. Patients hospitalized with COVID-19 from 1 March to 22 April 2020 were included into study population. The association between baseline variables and risk of in-hospital mortality was assessed through multivariable logistic regression and competing risk analyses., Results: Out of 1401 patients admitted at the participating centres with confirmed diagnosis of COVID-19, 226 (16.1%) underwent transthoracic echocardiography (TTE) and were included in the present analysis. In-hospital death occurred in 68 patients (30.1%). At multivariable analysis, left ventricular ejection fraction (LVEF, P < .001), tricuspid annular plane systolic excursion (TAPSE, P < .001) and ARDS (P < .001) were independently associated with in-hospital mortality. At competing risk analysis, we found a significantly higher risk of mortality in patients with ARDS vs those without ARDS (HR: 7.66; CI: 3.95-14.8), in patients with TAPSE ≤17 mm vs those with TAPSE >17 mm (HR: 5.08; CI: 3.15-8.19) and in patients with LVEF ≤50% vs those with LVEF >50% (HR: 4.06; CI: 2.50-6.59)., Conclusions: TTE might be a useful tool in risk stratification of patients with COVID-19. In particular, reduced LVEF and reduced TAPSE may help to identify patients at higher risk of death during hospitalization., (© 2021 The Authors. European Journal of Clinical Investigation published by John Wiley & Sons Ltd on behalf of Stichting European Society for Clinical Investigation Journal Foundation.)

Acute coronary syndromes (ACS) are frequently reported in patients with coronavirus disease 2019 (COVID-19) and may impact patient clinical course and mortality. Although the underlying pathogenesis remains unclear, several potential mechanisms have been hypothesized, including oxygen supply/demand imbalance, direct viral cellular damage, systemic inflammatory response with cytokine-mediated injury, microvascular thrombosis, and endothelial dysfunction. The severe hypoxic state, combined with other conditions frequently reported in COVID-19, namely sepsis, tachyarrhythmias, anemia, hypotension, and shock, can induce a myocardial damage due to the mismatch between oxygen supply and demand and results in type 2 myocardial infarction (MI). In addition, COVID-19 promotes atherosclerotic plaque instability and thrombus formation and may precipitate type 1 MI. Patients with severe disease often show decrease in platelets count, higher levels of d-dimer, ultralarge von Willebrand factor multimers, tissue factor, and prolongation of prothrombin time, which reflects a prothrombotic state. An endothelial dysfunction has been described as a consequence of the direct viral effects and of the hyperinflammatory environment. The expression of tissue factor, von Willebrand factor, thromboxane, and plasminogen activator inhibitor-1 promotes the prothrombotic status. In addition, endothelial cells generate superoxide anions, with enhanced local oxidative stress, and endothelin-1, which affects the vasodilator/vasoconstrictor balance and platelet aggregation. The optimal management of COVID-19 patients is a challenge both for logistic and clinical reasons. A deeper understanding of ACS pathophysiology may yield novel research insights and therapeutic perspectives in higher cardiovascular risk subjects with COVID-19., Competing Interests: The authors declare that they have no conflicts of interest. The authors have no commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Luca Esposito et al.)

Background: Laparoscopic rectal resection (LRR) for cancer is a challenging procedure, with conversion to open surgery being reported in up to 30% of cases. Since only a few studies with short follow-up have compared converted LRR and open RR (ORR), it is unclear if conversion to open surgery should be prevented by preferring an open approach in those patients with preoperatively known risk factors for conversion. The aim of this study was to compare early postoperative outcomes and long-term survival after completed LRR, converted LRR or ORR for non-metastatic rectal cancer., Methods: A prospective database of consecutive curative LRRs and ORRs for rectal cancer was reviewed. Patients undergoing LRR who required conversion (CONV group) were compared with those who had primary open rectal surgery (OPEN group) and completed LRR (LAP group). A multivariate analysis was performed to identify predictors of poor survival., Results: A total of 537 patients were included in the study: 272 in the LAP group, 49 in the CONV group and 216 in the OPEN group. There were no significant differences in perioperative morbidity, mortality and length of hospital stay between the three groups. Five-year overall survival and disease-free survival rates did not significantly differ between LAP, CONV and OPEN patients: 83.9 versus 77.8 versus 81% (P = 0.398) and 74.5 versus 62.9 versus 72.7% (P = 0.145), respectively. Similar 5-year OS and DFS rates were observed between patients who had converted LRR for locally advanced tumor or for non-tumor-related reasons: 81.2 versus 80.8% (P = 0.839) and 62.5 versus 63.7% (P = 0.970), respectively. Poor grade of tumor differentiation, lymphovascular invasion and a lymph node ratio of 0.25 or greater, but not conversion, were independently associated with poorer survival., Conclusion: Conversion to open surgery does not impair short-term outcomes and does not jeopardize 5-year survival in patients with rectal cancer when compared to primary open surgery.

Proteins frequently assume complex three-dimensional structures characterized by marginal thermodynamic stabilities. In this scenario, deciphering the folding code of these molecular giants with clay feet is a cumbersome task. Studies performed in last years have shown that the interplay between backbone geometry and local conformation has an important impact on protein structures. Although the variability of several geometrical parameters of protein backbone has been established, the role of the structural context in determining these effects has been hitherto limited to the valence bond angle τ (NC α C). We here investigated the impact of different factors on the observed variability of backbone geometry and peptide bond planarity. These analyses corroborate the notion that the local conformation expressed in terms of ( ϕ , ψ ) dihedrals plays a predominant role in dictating the variability of these parameters. The impact of secondary structure is limited to bond angles which involve atoms that are usually engaged in H-bonds and, therefore, more susceptible to the structural context. Present data also show that the nature of the side chain has a significant impact on angles such as NC α C β and C β C α C. In conclusion, our analyses strongly support the use of variability of protein backbone geometry in structure refinement, validation, and prediction.

Several investigations performed in the last two decades have unveiled that geometrical parameters of protein backbone show a remarkable variability. Although these studies have provided interesting insights into one of the basic aspects of protein structure, they have been conducted on globular and water-soluble proteins. We report here a detailed analysis of backbone geometrical parameters in nonglobular proteins/peptides. We considered membrane proteins and two distinct fibrous systems (amyloid-forming and collagen-like peptides). Present data show that in these systems the local conformation plays a major role in dictating the amplitude of the bond angle N-C(α)-C and the propensity of the peptide bond to adopt planar/nonplanar states. Since the trends detected here are in line with the concept of the mutual influence of local geometry and conformation previously established for globular and water-soluble proteins, our analysis demonstrates that the interplay of backbone geometrical parameters is an intrinsic and general property of protein/peptide structures that is preserved also in nonglobular contexts. For amyloid-forming peptides significant distortions of the N-C(α)-C bond angle, indicative of sterical hidden strain, may occur in correspondence with side chain interdigitation. The correlation between the dihedral angles Δω/ψ in collagen-like models may have interesting implications for triple helix stability.

Recent seminal investigations have suggested that the basic structural motif of amyloid fibers may be constituted by a tight association of two facing beta-sheets (steric zipper). Although this model has been derived from crystal structures of small peptide models, several theoretical investigations, essentially focused on steric zipper interface containing large polar and/or aromatic side chains, have confirmed the stability of this motif in a crystal-free context. To analyze the general validity of these findings, we carried out molecular dynamics (MD) simulations on aggregates stabilized by steric zipper interfaces made also of small or hydrophobic residues. In particular, we here characterized assemblies formed by the peptides SSTSAA and VQIVYK, whose structures have been recently solved at high resolution. In contrast to previous results obtained for polar/aromatic aggregates of the same size and with similar interface area, steric zipper assemblies composed of a pair of 10-stranded beta-sheets show high fluctuations and significant distortions in the simulation timescales (40-60 ns). Taking into account the crystal packing, the effect of the addition of an extra sheet to the assemblies was also evaluated. The MD results indicate that this addition does not provide extra-stabilization to the pair of sheet models. Although present data do not preclude the possibility that the steric zipper association identified in the crystal structure is the basic motif of SSTSAA and VQIVYK fibers, our findings highlight the importance of the nature of residues directly involved in the motif. Indeed, polar and aromatic residues that may form intrasheet and intersheet interactions likely provide a strong contribution to the steric zipper motif stability. Along this line, assemblies endowed with hydrophobic residues presumably require larger interfaces. In line with this suggestion, MD analysis of the HET-s(218-289) prion models composed of a similar number of strands shows that the assembly is endowed with a remarkable stability.

Few long-term studies have yet described neuropsychological outcome in preterm twins. Our aim was to assess, by long-term evaluation, neuropsychological outcome in preterm twins in order to define a correct follow-up program. Our study was a cohort one, with an index and a comparison group. Neonatal medical records of all preterm newborns admitted to our centre between 1991 and 1997 were reviewed and selected patients were recalled. The sample population included two matched groups of children aged 6-12 years, 86 twins and 86 singletons, submitted to paediatric, neurological, psychological, and ophthalmological examinations. Inclusion criteria were twin pregnancy and gestational age 27-36 weeks for index group; same gestational age, but single pregnancy, for the comparison group. All children underwent paediatric and neuropsychiatric examinations, cognitive assessment, and psychological evaluation by standardized tests for screening of learning specific disorders and language difficulties, and finally, ophthalmological examination. In order to study their role in predicting neuropsychological outcome, we examined some perinatal prognostic factors by statistical analysis. Unfavourable neuropsychological outcome was observed in 55/172 (32%) children, with different prevalence in the two groups, 42/172 (24%) in twins and 13/172 (8%) in singletons. Statistical analysis performed for examined prognostic factors showed significant differences in neuropsychological outcome with regard only to gestational age < 32 weeks, low birth weight, intraventricular haemorrhage, and periventricular leukomalacia. The incidence of neuropsychological diseases in the two groups showed significant difference about language and learning difficulties. Our data suggest that preterm twins represent a particular high-risk category of premature babies, mostly regarding the risk of so-called "minimal brain dysfunction", so a careful follow-up is recommended.