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Knee arthroplasty, commonly performed to treat osteoarthritis, necessitates precise surgical techniques for optimal outcomes. The introduction of systems such as the Persona Knee System (Zimmer Biomet, Warsaw, IN, USA) has revolutionized knee arthroplasty, promising enhanced precision and better patient outcomes. This study investigates the application of robotic planning specifically in knee prosthetic surgeries, with a focus on Persona Knee System prostheses. We conducted a retrospective analysis of 300 patients who underwent knee arthroplasty using the Persona Knee System between January 2020 and November 2023, including demographic data, surgical parameters, and preoperative imaging. Robotic planning was employed to simulate surgical procedures. The planning process integrated preoperative imaging data from a specific program adopted for conducting digital preoperative planning, and statistical analyses were conducted to assess correlations between patient characteristics and surgical outcomes. Out of 300 patients, 85% presented with minor deformities, validating the feasibility of robotic planning. Robotic planning demonstrated precise prediction of optimal arthroplasty sizes and alignment, closely aligning with preoperative imaging data. This study highlights the potential benefits of robotic planning in knee arthroplasty surgeries, particularly in cases with minor deformities. By leveraging preoperative imaging data and integrating advanced robotic technologies, surgeons can improve precision and efficacy in knee arthroplasty. Moreover, robotic technology allows for a reduced level of constraint in the intraoperative choice between Posterior-Stabilized and Constrained Posterior-Stabilized liners compared with an imageless navigated procedure., Competing Interests: F.B. and SMP.R. declare a teaching contract with the manufacturer (Zimmer Biomet). The other authors declare no conflicts of interest related to the present study.

Background : Pelvic insufficiency fractures (PIF) are typical in geriatric populations with reduced bone quality, most commonly in elderly postmenopausal women. These fractures are usually caused by low-energy forces over the bones during ordinary life and cause disabling pain. Treatment options range from conservative to operative. The aim of this study is to assess the outcomes of treatments for pelvic insufficiency fractures, determining optimal approaches between surgical intervention and conservative management. Methods : This literature review systematically examines articles focusing on patients with PIF, following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines, and using PubMed, Medline, and the Cochrane Library database. We took into account only full-text articles in indexed journals with available English abstracts, considering data about patient demographics, surgery, and outcomes. Results: After screening 128 articles, this study reviewed 20 manuscripts involving 1499 patients, mostly elderly females and focusing on sacrum fractures. Common treatments included conservative methods and sacroplasty, with a few complications reported. Osteoporosis was the prevalent comorbidity, and the survival rate post-treatment was high at 92.3%. Mobility outcomes varied, with some patients experiencing significant autonomy loss. The average follow-up period was over 17 months. Conclusions : This study found a cautious approach to surgery (timing of three weeks), which is reserved only for specific patterns, and it leads to increased autonomy and a lower risk of mortality. Due to the lack of pre- and postoperative scores as well as conflicting results, it is imperative to undertake further studies and research to be able to compare the alternative treatments efficiently.

Purpose: The exponential increase in total hip arthroplasty (THA) has led to acute and chronic surgery-related complications. Common chronic and local complications are represented by hip ossification (HO). The aim of our study was to assess the clinical and radiological correlates of patients undergoing surgical removal of heterotopic ossifications after THA and the possible association between HO and prosthetic joint infection., Methods: Data of 26 patients who underwent surgical removal of periprosthetic calcifications after THA from 2000 to 2022 were analyzed and compared with characteristics of 156 subjects without HO., Results: The preoperative radiographs of patients showed a high-grade Brooker, 3 or 4, later reduced to 1 or 2 in the postoperative radiographs. Ten (38.5%) patients underwent radiotherapy prophylaxis, administered as a single dose 24 h before surgery. In 19 (73%) patients, pharmacological prophylaxis with indomethacin was added in the 30 postoperative days. Only one patient who underwent radiotherapy had a recurrence, while new ossifications were found in three patients without prophylaxis (11.5%). Intraoperative cultures were performed for suspected periprosthetic infection in 8 study group patients. In logistic regression, the presence of HO was significantly and inversely associated with the ASA score (OR = 0.27, 95% CI = 0.09-0.82; P = 0.021) after adjusting., Conclusion: Surgical HO removal in symptomatic patients with high-grade disease produces good clinical and radiographic results. Radiotherapy was a good perioperative and preventive strategy for recurrence, also associated with NSAIDs and COX-2 inhibitors., (© 2023. The Author(s) under exclusive licence to SICOT aisbl.)

Molecular electronic spins are good candidates as qubits since they are characterized by a large tunability of their electronic and magnetic properties through a rational chemical design. Coordination compounds of light transition metals are promising systems for spin-based quantum information technologies, thanks to their long spin coherence times up to room temperature. Our work aims at presenting an in-depth study on how the spin-phonon coupling in vanadyl-acetylacetonate, [VO(acac) 2 ], can change as a function of temperature using terahertz time-domain spectroscopy and density functional theory (DFT) calculations. Powder THz spectra were recorded between 10 and 300 K. The temperature dependence of vibrational frequencies was then accounted for in the periodic DFT calculations using unit-cell parameters measured at two different temperatures and the optimized ones, as usually reported in the literature. In this way, it was possible to calculate the observed THz anharmonic frequency shift with high accuracy. The overall differences in the spin-phonon coupling magnitudes as a function of temperature were also highlighted showing that the computed trends have to be ascribed to the anisotropic variation of cell parameters., Competing Interests: The authors declare no competing financial interest., (© 2021 The Authors. Published by American Chemical Society.)

Despite water being the most common and most widely studied substance in the world, it still presents unknown aspects. In particular, water shows several thermodynamic and dynamical anomalies in the liquid and supercooled metastable phases, and the natures of these phases are still hotly debated. Here, we report measurements of water using the optical Kerr effect as a function of pressure along two isotherms, at 273 K from 0.1 to 750 MPa and at 297 K from 0.1 to 1350 MPa, reaching the supercooled metastable phase. The structural relaxation and the low frequency vibrational dynamics of water show a peculiar pressure dependence similar to that of other dynamical properties. The data analysis suggests the presence in the water phase diagram of a crossover area that divides two regions characterized by different dynamic regimes, which appear to be related to two liquid forms, one dominated by the high density water and the other by the low density water.

Background: Because of a lack of large-scale prospective studies there is no clear indication about the management of patients with small bowel adenocarcinoma (SBA). This study evaluated clinical outcome of patients diagnosed with SBA at our institution., Methods: Clinicopathologic features, treatments, and clinical outcome of patients diagnosed with SBA between 2006 and 2017 were retrospectively analyzed. Median time of survival was calculated and compared using the log-rank test. Multivariate Cox regression was used to test independence of significant factors in univariate analysis., Results: Forty patients were included in the study; the majority (82.5%) had a tumor in the duodenum (including ampulla of Vater) and an early stage disease at the diagnosis. Median overall survival (OS) in the whole study population was 26.5 months. Patients with a tumor of the lower part of the small intestine (jejunum, ileum, and appendix) showed a better OS compared with that of patients with upper SBA (40 months vs 26 months, respectively; P =0.09). Primary tumor site and stage were independent predictors of OS., Conclusions: Our results suggest a prognostic role for the primary tumor site. This finding deserves to be further investigated to ensure better classification as well as more effective management strategies for SBA.

The photophysics of 9(19),16(17),23(24)-tri-tert-butyl-2-[ethynyl-(4-carboxymethyl)phenyl]phthalocyaninatozinc(ii) and its H-aggregates is studied in different solvents by means of ultrafast non-linear optical spectroscopy and computational modeling. In non-coordinating solvents, both stationary and time-resolved spectroscopies highlight the formation of extended molecular aggregates, whose dimension and spectral properties depends on the concentration. In all the explored experimental conditions, time-resolved transient absorption experiments show multi exponential decay of the signals. Additional insights into the excited state relaxation mechanisms of the system is obtained with 2D electronic spectroscopy, which is employed to compare the deactivation channels in the absence or presence of aggregates. In ethanol and diethylether, where only monomers are present, an ultrafast relaxation process among the two non-degenerate Q-states of the molecule is evidenced by the appearance of a cross peak in the 2D-maps. In chloroform or CCl4, where disordered H-aggregates are formed, an energy transfer channel among aggregates with different composition and size is observed, leading to the non-radiative decay towards the lower energy dark state of the aggregates. Efficient coupling between less and more aggregated species is highlighted in two-dimensional electronic spectra by the appearance of a cross peak. The kinetics and intensity of the latter depend on the concentration of the solution. Finally, the linear spectroscopic properties of the aggregate are reproduced using a simplified structural model of an extended aggregate, based on Frenkel Hamiltonian Calculations and on an estimate of the electronic couplings between each dimer composing the aggregate computed at DFT level.

Here we report the investigation of the magnetization dynamics of a vanadyl complex with diethyldithiocarbamate (Et 2 dtc - ) ligands, namely [VO(Et 2 dtc) 2 ] (1), in both solid-state and frozen solution. This showed an anomalous and unprecedentedly observed field dependence of the relaxation time, which was modeled with three contributions to the relaxation mechanism. The temperature dependence of the weight of the two processes dominating at low fields was found to well correlate with the low energy vibrations as determined by THz spectroscopy. This detailed experimental comparative study represents a fundamental step to understand the spin dynamics of potential molecular quantum bits, and enriches the guidelines to design molecule-based systems with enhanced quantum coherence.

Clarifying the structure/dynamics relation of water hydrogen-bond network has been the aim of extensive research over many decades. By joining anvil cell high-pressure technology, femtosecond 2D infrared spectroscopy, and molecular dynamics simulations, we studied, for the first time, the spectral diffusion of the stretching frequency of an HOD impurity in liquid water as a function of pressure. Our experimental and simulation results concordantly demonstrate that the rate of spectral diffusion is almost insensitive to the applied pressure. This behavior is in contrast with the previously reported pressure-induced speed up of the orientational dynamics, which can be rationalized in terms of large angular jumps involving sudden switching between two hydrogen-bonded configurations. The different trend of the spectral diffusion can be, instead, inferred considering that the first solvation shell preserves the tetrahedral structure with pressure and the OD stretching frequency is only slight perturbed.

In recent years, metronomic chemotherapy, consisting of continuous administration of low doses of cytotoxic agents, has being used as rescue therapy for different tumours. The aim of this study was to retrospectively assess the efficacy and safety of low-dose metronomic, oral capecitabine in pretreated or frail patients with recurrent upper gastrointestinal tract cancer. Patients with pretreated upper gastrointestinal tract cancer or who were not candidates for standard chemotherapy because of toxicity concerns received capecitabine at 1500 mg per day continuously until disease progression or occurrence of toxicity. Forty-seven patients (25 oesophagogastric cancer, 22 pancreatobiliary cancer; 25 men, 22 women; median age 69 years, range 42-90) were included in the study. Forty-five percent of the patients had received at least two previous lines of treatment and the median number of previous treatments was 1 (range 0-5). Twelve (31.6%) patients achieved clinical benefit (one partial response, 11 stable disease), whereas nine (23.7%) patients were progression free for at least 6 months. In an exploratory analysis, there was a significant relationship between performance status and clinical benefit (hazard ratio=8.25; P=0.01). The median overall survival was 5 months. A good performance status was associated with a longer survival (hazard ratio=0.26; P<0.01). No severe toxicity or treatment-related death was reported. Metronomic capecitabine showed good safety and moderate activity in frail or pretreated patients with advanced, upper gastrointestinal tract cancer.

By means of one- and two-dimensional transient infrared spectroscopy and femtosecond stimulated Raman spectroscopy, we investigated the excited state dynamics of peridinin, a carbonyl carotenoid occurring in natural light harvesting complexes. The presence of singly and doubly excited states, as well as of an intramolecular charge transfer (ICT) state, makes the behavior of carbonyl carotenoids in the excited state very complex. In this work, we investigated by time resolved spectroscopy the relaxation of photo-excited peridinin in solvents of different polarities and as a function of the excitation wavelength. Our experimental results show that a characteristic pattern of one- and two-dimensional infrared bands in the C=C stretching region allows monitoring the relaxation pathway. In polar solvents, moderate distortions of the molecular geometry cause a variation of the single/double carbon bond character, so that the partially ionic ICT state is largely stabilized by the solvent reorganization. After vertical photoexcitation at 400 nm of the S2 state, the off-equilibrium population moves to the S1 state with ca. 175 fs time constant; from there, in less than 5 ps, the non-Franck Condon ICT state is reached, and finally, the ground state is recovered in 70 ps. That the relevant excited state dynamics takes place far from the Franck Condon region is demonstrated by its noticeable dependence on the excitation wavelength.

Using heterodyne-detected optical Kerr effect (HD-OKE) measurements, we investigate the vibrational dynamics and the structural relaxation of water nanoconfined in Vycor porous silica samples (pore size ≃ 4 nm) at different levels of hydration and temperatures. At low levels of hydration corresponding to two complete superficial water layers, no freezing occurs and the water remains mobile at all the investigated temperatures with dynamic features similar, but not equal to, the bulk water. The fully hydrated sample shows the formation of ice at about 248 K. This process does not involve all the contained water; a part of it remains in a supercooled phase. The structural relaxation times measured from the decay of the time-dependent HD-OKE signal shows the temperature dependence largely affected by the hydration level; the low frequency (ν < 500 cm(-1)) vibrational spectra obtained by the Fourier transforms of the HD-OKE signal appear less affected by confinement.

Assigning the vibrational modes of molecules in the electronic excited state is often a difficult task. Here we show that combining two nonlinear spectroscopic techniques, transient 2D exchange infrared spectroscopy (T2D-IR-EXSY) and femtosecond stimulated Raman spectroscopy (FSRS), the contribution of the C═C and C═O modes in the excited-state vibrational spectra of trans-β-apo-8'-carotenal can be unambiguously identified. The experimental results reported in this work confirm a previously proposed assignment based on quantum-chemical calculations and further strengthen the role of an excited state with charge-transfer character in the relaxation pathway of carbonyl carotenoids. On a more general ground, our results highlight the potentiality of nonlinear spectroscopic methods based on the combined use of visible and infrared pulses to correlate structural and electronic changes in photoexcited molecules.

The aim of the study was to retrospectively assess the efficacy and safety of low-dose metronomic oral capecitabine in pretreated or frail patients with recurrent colorectal cancer. Patients with recurrent colorectal cancer and prior treatment with fluoropyrimidines, oxaliplatin, and irinotecan or unable to receive standard chemotherapy because of toxicity concerns were included. Treatment consisted of oral capecitabine 1,500 mg daily until disease progression or unacceptable toxicity. Response rates were determined according to RECIST criteria. The end points were disease control rate [(DCR) consisting of complete response, partial response (PR), and stable disease (SD)], overall survival (OS), and safety. Sixty-eight patients, median age 72.5 years, were treated. The median number of previous treatments was 2 (range 0-5). Sixty-two percent of patients had received ≥2 previous lines of treatment. The overall DCR was 26%, PR in 2 (3%) and SD in 14 (23%). Nineteen percent of patients were progression free for at least 6 months. In an exploratory analysis, there was a significant relation of performance status with DCR (HR = 3.3; P = 0.05). The median OS was 8 months. DCR was associated with a longer survival (HR = 0.4; P < 0.01). Grade 3 toxicities included anemia (1), diarrhea (1), and hand-foot syndrome (1). There were no cases of grade 4 toxicity or treatment-related deaths. Metronomic capecitabine was moderately active and well-tolerated in pretreated or frail patients with recurrent colorectal cancer.

In this work we analyzed the infrared and visible transient absorption spectra of all-trans-β-apo-8'-carotenal in several solvents, differing in both polarity and polarizability at different excitation wavelengths. We correlate the solvent dependence of the kinetics and the band shape changes in the infrared with that of the excited state absorption bands in the visible, and we show that the information obtained in the two spectral regions is complementary. All the collected time-resolved data can be interpreted in the frame of a recently proposed relaxation scheme, according to which the major contributor to the intramolecular charge transfer (ICT) state is the bright 1Bu(+) state, which, in polar solvents, is dynamically stabilized through molecular distortions and solvent relaxation. A careful investigation of the solvent effects on the visible and infrared excited state bands demonstrates that both solvent polarity and polarizability have to be considered in order to rationalize the excited state relaxation of trans-8'-apo-β-carotenal and clarify the role and the nature of the ICT state in this molecule. The experimental observations reported in this work can be interpreted by considering that at the Franck-Condon geometry the wave functions of the S1 and S2 excited states have a mixed ionic/covalent character. The degree of mixing depends on solvent polarity, but it can be dynamically modified by the effect of polarizability. Finally, the effect of different excitation wavelengths on the kinetics and spectral dynamics can be interpreted in terms of photoselection of a subpopulation of partially distorted molecules.

Solutions containing 8 and 32 wt% myoglobin are studied by means of infrared spectroscopy, as a function of temperature (290 K and lower temperatures), in the mid- and far-infrared spectral range. Moreover, ultrafast time-resolved infrared measurements are performed at ambient temperature in the O-D stretching region. The results evidence that the vibrational properties of water remain the same in these myoglobin solutions (anharmonicity, vibrational relaxation lifetime…) and in neat water. However, the collective properties of the water molecules are significantly affected by the presence of the protein: the orientational time increases, the solid-liquid transition is affected in the most concentrated solution and the dynamical transition of the protein is observed, from the point of view of water, even in the least concentrated solution, proving that the water and myoglobin dynamics are coupled.

Pressure is extremely efficient to tune intermolecular interactions, allowing the study of the mechanisms regulating, at the molecular level, the structure and dynamics of condensed phases. Among the simplest molecules, water represents in many respects a mystery despite its primary role in ruling most of the biological, physical, and chemical processes occurring in nature. Here we report a careful characterization of the dynamic regime change associated with low-density and high-density forms of liquid water by measuring the line shape of the OD stretching mode of HOD in liquid water along different isotherms as a function of pressure. Remarkably, the high-pressure studies have been here extended down to 240 K, well inside the supercooled regime. Supported by molecular dynamics simulations, a correlation among amorphous and crystalline solids and the two different liquid water forms is attempted to provide a unified picture of the metastable and thermodynamic regimes of water.

Lung cancer is the leading cause of cancer-related death around the world; the addition of chemotherapy to treatment of this disease has been shown to significantly increase progression-free survival and overall survival. Despite newer chemotherapies, it is important to personalize the care (treatment and dose) upon each single patient's susceptibility for controlling and reducing adverse side-effects, at best. The present review describes the current status of pharmacogenomics studies regarding germline DNA variants that may alter response and tolerability to chemotherapeutic agents used to treat lung cancer, including perspective studies., (Copyright© 2014 International Institute of Anticancer Research (Dr. John G. Delinassios), All rights reserved.)

The time-resolved optical Kerr effect spectroscopy (OKE) is a powerful experimental tool enabling accurate investigations of the dynamic phenomena in molecular liquids. We introduced innovative experimental and fitting procedures, that enable a safe deconvolution of sample response function from the instrumental function. This is a critical issue in order to measure the dynamics of liquid water. We report OKE data on water measuring intermolecular vibrations and the structural relaxation processes in an extended temperature range, inclusive of the supercooled states. The unpreceded data quality makes possible a solid comparison with few theoretical models: the multi-mode Brownian oscillator model, the Kubo's discrete random jump model, and the schematic mode-coupling model. All these models produce reasonable good fits of the OKE data of stable liquid water, i.e., over the freezing point. The features of water dynamics in the OKE data becomes unambiguous only at lower temperatures, i.e., for water in the metastable supercooled phase. We found that the schematic mode-coupling model provides the more rigorous and complete model for water dynamics, even if its intrinsic hydrodynamic approach does not give a direct access to the molecular information.

The excited state dynamics of carbonyl carotenoids is very complex because of the coupling of single- and doubly excited states and the possible involvement of intramolecular charge-transfer (ICT) states. In this contribution we employ ultrafast infrared spectroscopy and theoretical computations to investigate the relaxation dynamics of trans-8'-apo-β-carotenal occurring on the picosecond time scale, after excitation in the S2 state. In a (slightly) polar solvent like chloroform, one-dimensional (T1D-IR) and two-dimensional (T2D-IR) transient infrared spectroscopy reveal spectral components with characteristic frequencies and lifetimes that are not observed in nonpolar solvents (cyclohexane). Combining experimental evidence with an analysis of CASPT2//CASSCF ground and excited state minima and energy profiles, complemented with TDDFT calculations in gas phase and in solvent, we propose a photochemical decay mechanism for this system where only the bright single-excited 1Bu(+) and the dark double-excited 2Ag(-) states are involved. Specifically, the initially populated 1Bu(+) relaxes toward 2Ag(-) in 200 fs. In a nonpolar solvent 2Ag(-) decays to the ground state (GS) in 25 ps. In polar solvents, distortions along twisting modes of the chain promote a repopulation of the 1Bu(+) state which then quickly relaxes to the GS (18 ps in chloroform). The 1Bu(+) state has a high electric dipole and is the main contributor to the charge-transfer state involved in the dynamics in polar solvents. The 2Ag(-) → 1Bu(+) population transfer is evidenced by a cross peak on the T2D-IR map revealing that the motions along the same stretching of the conjugated chain on the 2Ag(-) and 1Bu(+) states are coupled.

Carbon monoxide recombination dynamics in a mutant of the truncated hemoglobin from Thermobida fusca (3F-Tf-trHb) has been analyzed by means of ultrafast Visible-pump/MidIR-probe spectroscopy and compared with that of the wild-type protein. In 3F-Tf-trHb, three topologically relevant amino acids, responsible for the ligand stabilization through the formation of a H-bond network (TyrB10 TyrCD1 and TrpG8), have been replaced by Phe residues. X-ray diffraction data show that Phe residues in positions B10 and G8 maintain the same rotameric arrangements as Tyr and Trp in the wild-type protein, while Phe in position CD1 displays significant rotameric heterogeneity. Photodissociation of the ligand has been induced by exciting the sample with 550 nm pump pulses and the CO rebinding has been monitored in two mid-IR regions respectively corresponding to the ν(CO) stretching vibration of the iron-bound CO (1880-1980 cm(-1)) and of the dissociated free CO (2050-2200 cm(-1)). In both the mutant and wild-type protein, a significant amount of geminate CO rebinding is observed on a subnanosecond time scale. Despite the absence of the distal pocket hydrogen-bonding network, the kinetics of geminate rebinding in 3F-Tf-trHb is very similar to the wild-type, showing how the reactivity of dissociated CO toward the heme is primarily regulated by the effective volume and flexibility of the distal pocket and by caging effects exerted on the free CO on the analyzed time scale.

In this work we present the synthesis, time-resolved spectroscopic characterization and computational analysis of a bichromophore composed of two very well-known naturally occurring dyes: 7-hydroxycoumarin (umbelliferone) and 1,2-dihydroxyanthraquinone (alizarin). The umbelliferone donor (Dn) and alizarin acceptor (Ac) moieties are linked to a triazole ring viaσ bonds, providing a flexible structure. By measuring the fluorescence quantum yields and the ultrafast transient absorption spectra we demonstrate the high efficiency (∼85%) and the fast nature (∼1.5 ps) of the energy transfer in this compound. Quantum chemical calculations, within the density functional theory (DFT) approach, are used to characterize the electronic structure of the bichromophore (Bi) in the ground and excited states. We simulate the absorption and fluorescence spectra using the TD-DFT methods and the vertical gradient approach (VG), and include the solvent effects by adopting the conductor-like polarizable continuum model (CPCM). The calculated electronic structure suggests the occurrence of weak interactions between the electron densities of Dn and Ac in the excited state, indicating that the Förster-type transfer is the appropriate model for describing the energy transfer in this system. The average distance between Dn and Ac moieties calculated from the conformational analysis (12 Å) is in very good agreement with the value estimated from the Förster equation (∼11 Å). At the same time, the calculated rate constant for energy transfer, averaged over multiple conformations of the system (3.6 ps), is in reasonable agreement with the experimental value (1.6 ps) estimated by transient absorption spectroscopy. The agreement between experimental results and computational data leads us to conclude that the energy transfer in Bi is well described by the Förster mechanism.

We have studied the effect of transient vibrational inversion of population in trans-β-apo-8(')-carotenal on the time-resolved femtosecond stimulated Raman scattering (TR-FSRS) signal. The experimental data are interpreted by applying a quantum mechanical approach, using the formalism of projection operators for constructing the theoretical model of TR-FSRS. Within this theoretical frame we explain the presence of transient Raman losses on the Stokes side of the TR-FSRS spectrum as the effect of vibrational inversion of population. In view of the obtained experimental and theoretical results, we conclude that the excited S2 electronic level of trans-β-apo-8(')-carotenal relaxes towards the S0 ground state through a set of four vibrational sublevels of S1 state.

Lung cancer is the leading cause of cancer-related death worldwide, with approximately 1.2 million deaths annually. The standard-of-care in patients with advanced disease is platinum-based doublet chemotherapy. Recent advances in the understanding of biological mechanisms of tumor growth have allowed for identification of some molecular targets for cancer treatment, such as vascular endothelial growth factor (VEGF) and epidermal growth factor receptor (EGFR). VEGF is a pro-angiogenetic factor, which binds membrane receptors, and whose intra-cytoplasmatic domain presents tyrosine kinase activity. Pathological angiogenesis promotes tumor growth and metastasis. Targeted action against angiogenesis can lead to regression or normalization of neovascular structures and to inhibition of new blood vessel growth. The most commonly used mechanism is mediated by bevacizumab, a monoclonal antibody that selectively binds to VEGF and prevents interaction with its receptor. Currently bevacizumab is the only anti-angiogenic agent approved for the first-line treatment of non-small cell lung cancer (NSCLC) in selected patients. In the present review, we discuss the most important trials that demonstrate the efficacy and safety of bevacizumab. We also present an overview of the types of patients eligible for this treatment and a cost-effectiveness analysis. In conclusion, the possibility of administering a treatment with bevacizumab must be carefully analyzed case by case. It is important to identify those patients who can really benefit from the use of this drug, through the identification of specific response markers.

While tetracyclines are in active medical use, their bioactive atomic compositions are still questionable. Here, we investigate the structural properties of neutral tetracycline in dimethyl sulfoxide - the environment used often to mimic the environment in vivo. We compare the measured linear and nonlinear infrared spectra to those calculated for a collection of stable and energetically plausible tautomers, and describe the structurally sensitive off-diagonal peaks using anharmonicities of the normal modes. The comparison of experimental and theoretical 2DIR spectra is consistent with the numerical predictions of statistical thermodynamics on the relative weights of possible tautomers. In result, we provide the systematic account of the structural realizations of neutral tetracycline in DMSO.

Liquid water has a primary role in ruling life on Earth in a wide temperature and pressure range as well as a plethora of chemical, physical, geological, and environmental processes. Nevertheless, a full understanding of its dynamical and structural properties is still lacking. Water molecules are associated through hydrogen bonds, with the resulting extended network characterized by a local tetrahedral arrangement. Two different local structures of the liquid, called low-density (LDW) and high-density (HDW) water, have been identified to potentially affect many different chemical, biological, and physical processes. By combining diamond anvil cell technology, ultrafast pump-probe infrared spectroscopy, and classical molecular dynamics simulations, we show that the liquid structure and orientational dynamics are intimately connected, identifying the P-T range of the LDW and HDW regimes. The latter are defined in terms of the speeding up of the orientational dynamics, caused by the increasing probability of breaking and reforming the hydrogen bonds.

We present a case report of a 75-years-old woman affected by renal clear cell carcinoma with a synchronous pancreatic metastasis and a metachronous lung metastasis. This case has two peculiarities. First the pancreatic metastasis was treated just with medical therapy, that is, Sunitinib, instead of the surgical therapy that is mostly considered. Secondly, the pancreatic lesion showed different characteristics on the computed tomography scan compared to the usual pancreatic metastases from renal clear cell carcinoma. The pancreatic metastasis totally regressed after medical treatment and nowadays, four years after the diagnosis, the patient is disease-free.

In this work, we studied the valence tautomerism process on two different Co-dioxolene complexes by means of transient infrared spectroscopy (TRIR). The molecules investigated are ls-Co(III)(Cat-N-BQ)(Cat-N-SQ) (DQ2) and [ls-Co(III)(tpy)(Cat-N-SQ)]PF6 (tpy), where Cat-NBQ = 2-(2-hydroxy-3,5-ditert-butylphenyl-imino)-4,6-ditert-butylcyclohexa-3,5-dienone, Cat-N-SQ is the dianionic radical analogue, and tpy = 2,2'-6-2″-terpyridine. DFT calculations of the harmonic frequencies for the two complexes allow us to pinpoint the normal modes to be used as markers of the semiquinonate and benzoquinonate isomers. The photoinduced one-electron charge transfer process from the radical semiquinonate ligand to the metal center leads to a ls-Co(II)(x)(Cat-N-BQ) electronic state (where x is the other ligand). Following this first step, an ultrafast ISC process (τ < 200 fs) takes places, yielding the benzoquinonate isomer (hs-Co(II)(x)(Cat-N-BQ)). In the experiments, we employed different excitation wavelengths on resonance with different absorption bands of the two samples. Excitation in the ligand-to-metal charge transfer (LMCT) band at ∼520 nm and in the semiquinonate band at ∼1000 nm induces the valence tautomerism (VT) in both samples. From the time evolution of the TRIR spectra, we determine the time constants of the vibrational cooling in the tautomeric state (7-14 ps) and the ground state recovery times (∼350 ps for tpy and ∼450 ps for DQ2). In contrast, when the pump frequency is set at 712 nm, on resonance with the benzoquinonate absorption band of the second active ligand of the DQ2, no electron transfer takes place: the TRIR spectra basically show only ground state bleaching bands and no marker band of the tautomeric conversion shows up.

We report on experimental results of supercontinuum generation in bulk diamond. The spectrum of supercontinuum generated with 800 nm pump extends up to 600 nm towards short wavelengths. We present the numerical model explaining the phenomenon, in which the role of different nonlinear effects including stimulated Raman scattering is discussed. Unlike in other materials, in diamond the feature of supercontinuum due to stimulated Raman response is apparently visible.

The low frequency (nu < 500 cm(-1)) vibrational spectra of hydrated porous silica are specifically sensitive to the hydrogen bond interactions and provide a wealth of information on the structural and dynamical properties of the water contained in the pores of the matrix. We investigate systematically this spectral region for a series of Vycor porous silica samples (pore size approximately equal 4 nm) at different levels of hydration, from the dry matrix to completely filled pores. The spectra are obtained as the Fourier transforms of time-resolved heterodyne detected optical Kerr effect (HD-OKE) measurements. The comparison of these spectra with that of bulk water enables us to separately extract and analyze the spectral contributions of the first and second hydration layers, as well as that of bulk-like inner water. We conclude that the extra water entering the pores above approximately equal 10% water/silica weight ratio behaves very similarly to bulk water. At lower levels of hydration, corresponding to two complete superficial water layers or less, the H-bond bending and stretching bands, characteristic of the tetrahedral coordination of water in the bulk phase, progressively disappear: clearly in these conditions the H-bond connectivity is very different from that of liquid water. A similar behavior is observed for the structural relaxation times measured from the decay of the time-dependent HD-OKE signal. The value for the inner water is very similar to that of the bulk liquid; that of the first two water layers is definitely longer by a factor approximately equal 4. These findings should be carefully taken into account when employing pore confinement to extend towards lower temperatures the accessible temperature range of supercooled water.

The liquid and supercooled states of water show a series of anomalies whose nature is debated. A key role is attributed to the formation of structural aggregates induced by critical phenomena occurring deep in the supercooled region; the nature of the water anomalies and of the hidden critical processes remains elusive. Here we report a time-resolved optical Kerr effect investigation of the vibrational dynamics and relaxation processes in supercooled bulk water. The experiment measures the water intermolecular vibrations and the structural relaxation process in an extended temperature range, and with unprecedented data quality. A mode-coupling analysis of the experimental data enables to characterize the intermolecular vibrational modes and their interplay with the structural relaxation process. The results bring evidence of the coexistence of two local configurations, which are interpreted as high-density and low-density water forms, with an increasing weight of the latter at low temperatures.

Hydrogen bond interactions strongly affect vibrational properties and frequencies, the most common consequence being a redshift of the stretching vibration involved; there are, however, few exceptions to this general trend. In previous works, we have proved the effectiveness of ab initio simulations combined with wavelet analysis to investigate these effects and put them into relation to structural environment. In this work, we investigate the hydrogen bond effects on the structural and vibrational properties of 1,3-propanediol in acetonitrile by a combined experimental and computational approach. We explain the appearance of two spectral components in the O-H stretching band on the basis of intra- and intermolecular hydrogen bond interactions. We also elucidate the blueshift of the C≡N stretching band as due to a hydrogen bond interaction between the glycol and acetonitrile that modify the electron density distribution inside the CN group. This effect is well reproduced by ab initio molecular dynamics simulations and density functional calculations reported in this work.

Carbon monoxide recombination dynamics upon photodissociation with visible light has been characterized by means of ultrafast visible-pump/MidIR probe spectroscopy for the truncated hemoglobins from Thermobifida fusca and Bacillus subtilis. Photodissociation has been induced by exciting the sample at two different wavelengths: 400 nm, corresponding to the heme absorption in the B-band, and 550 nm, in the Q-bands. The bleached iron-CO coordination band located at 1850-1950 cm(-1) and the free CO absorption band in the region 2050-2200 cm(-1) have been observed by probe pulses tuned in the appropriate infrared region. The kinetic traces measured at 1850-1950 cm(-1) reveal multiexponential subnanosecond dynamics that have been interpreted as arising from fast geminate recombination of the photolyzed CO. A compared analysis of the crystal structure of the two proteins reveals a similar structure of their distal heme pocket, which contains conserved polar and aromatic amino acid residues closely interacting with the iron ligand. Although fast geminate recombination is observed in both proteins, several kinetic differences can be evidenced, which can be interpreted in terms of a different structural flexibility of the corresponding heme distal pockets. The analysis of the free CO band-shape and of its dynamic evolution brings out novel features about the nature of the docking site inside the protein cavity.

The hydrogen-bond dynamics of lithium nitrate trihydrate has been studied by a combined approach based on ab initio molecular dynamics simulations and wavelet analysis. The simultaneous bifurcated interaction between one hydrogen atom of water molecules and two oxygen atoms of nitrate ions is the pivotal feature of the crystal structure: this bifurcated interaction has deep effects on the O-H stretching region of the vibrational spectrum. The structural, dynamic, spectroscopic, and electronic properties of the bifurcated hydrogen bond have been investigated computationally, elucidating at the molecular level the differences with weak and strong hydrogen bonds present in the crystal. These studies corroborate the very recent IR experiments performed on the lithium nitrate trihydrate crystal, offering new perspectives to interpreting the vibrational spectra. In fact, this approach allows obtaining two-dimensional plots, which summarize the essential features of both the hydrogen-bond network and IR spectra, resulting in a peculiar "signature" of the bifurcated interaction.

In this work we present, to our knowledge for the first time, the results of a transient infrared spectroscopic study of the photoinduced valence tautomerism process in cobalt-dioxolene complexes with sub-picosecond time resolution. The molecular systems investigated were [Co(tpa)(diox)]PF(6) (1) and [Co(Me(3)tpa)(diox)]PF(6) (2), where diox = 3,5-di-tert-butyl-1,2-dioxolene; tpa = tris(2-pyridylmethyl)amine and Me(3)tpa its 6-methylated analogue. Complex (1) is present in solution as ls-Co(III)(catecholate) (1-CAT), while (2) as hs-Co(II)(semiquinonate) (2-SQ). DFT calculation of the harmonic frequencies for (1) and (2) allowed us to identify the vibrational markers of catecholate and semiquinonate redox isomers. Irradiation with 405 and 810 nm pulses (~35 fs) of (1-CAT) induces the formation of an intermediate excited species from which the ground state population is recovered with a time constant of 1.5 ± 0.3 ns. Comparing the 1 ns transient infrared spectrum with the experimental difference spectrum FTIR(2-SQ)-FTIR(1-CAT) and with the calculated difference spectrum IR(c)(1-SQ)-IR(c)(1-CAT) we are able to unequivocally identify the long lived species as the semiquinonate redox isomer of (1). On the other hand, no evidence of photoconversion is observed upon irradiation of (2) with 405 nm. Temporal evolution of transient spectra was analyzed with the combined approach consisting of singular values decomposition and global fitting (global analysis). After 405 and 810 nm excitation of (1-CAT), the semiquinonate excited species is formed on an ultrafast time scale (<200 fs) and cools down within the first 50 ps. Excitation of (2-SQ) with 405 nm wavelength produces a short lived excited state in which the semiquinonate nature of dioxolene is preserved and the ground state recovery is completed within 30 ps.

The linear and two-dimensional infrared (2DIR) responses of the amide I vibrational mode in liquid formamide are investigated experimentally and theoretically using molecular dynamics simulations. The recent method based on the numerical integration of the Schrödinger equation is employed to calculate the 2DIR spectra. Special attention is devoted to the interplay of the structural dynamics and the excitonic nature of the amide I modes in determining the optical response of the studied system. In particular, combining experimental data, simulated spectra and analysis of the simulated atomic trajectory in terms of a transition dipole coupling model, we provide a convincing explanation of the peculiar features of the 2DIR spectra, which show a substantial increase of the antidiagonal bandwidth with increasing frequency. We point out that, at variance with liquid water, the 2DIR spectral profile of formamide is determined more by the excitonic nature of the vibrational states than by the fast structural dynamics responsible for the frequency fluctuations.

The association of peptides to phospholipid membranes through the insertion of an anchoring hydrocarbon tail is common to some viruses and to several anticancer drugs. We investigate the association of an anchor dipeptide, N-myristoylated methyl glycine (MrG), to phospholipid membrane fragments made of 1-palmitoyl-2-linoleyl phosphatidylcholine (PLPC). Here we report on the experimental findings of two-dimensional infrared spectroscopy of an MrG backbone in the 6 μm wavelength region. The experimental outcomes are supported by ab initio calculations and by a molecular dynamics simulation accomplished with the replica exchange method. We find that the guest molecule has a preferential unfolded conformation, with dihedral angles Φ = -90 ± 20° and Ψ = -180 ± 20°, while the average orientational distribution of the amide I transition dipole moments with respect to the neighbor PLPC carbonyls is peaked at angles in the range 21-33°. The depth of penetration of MrG inside the membrane corresponds rather well to the one estimated in our previous paper [J. Phys. Chem. B, 2009, 113, 16246], where we found that the backbone moieties of MrG are localized slightly above the carbonyl groups of PLPC. According to the simulation results, the anchor tail is completely inserted in the hydrophobic region of the bilayer, with a largely prevalent extended conformation and a preferential alignment along the average direction of the PLPC hydrocarbon tails.

Background: Matrix-assisted laser desorption ionization time-of-flight (MALDI-TOF) proteomic signature might be of interest for the early detection and staging of hepatocellular carcinoma (HCC). However, published procedures have been criticized for the lack of data about analytical reproducibility, and the use of inadequate data processing., Methods: MALDI-TOF profiling of peptides bound to serum albumin ("albuminome") was performed using 90 μL of serum from 45 study subjects (HCV-related cirrhosis, small, unifocal HCCs and advanced HCCs). To overcome the large intra-sample variability, a Quality Assurance protocol was implemented, and 4-8 samples for each subject were processed and analyzed. Overall, 522 subject samples and 299 quality-control spectra were analyzed. A machine-learning approach (Random Forest) was applied to analyze the data sets., Results: Mean intra-sample coefficient of variation (CV) of the analytical procedure was 17.6%-30.0%; inter-subject CV was in the range 48.8%-71.3% among the three study groups. The Random Forest procedure correctly classified 433/522 "patient samples" and 295/299 "reference samples"; 43/45 patients were correctly classified following this approach., Conclusions: Our data suggest that, notwithstanding the large analytical variability found, multiple proteomic profiles obtained from each subject can differentiate cirrhosis with and without HCC, and HCCs with and without vascular invasion, warranting further investigation in a prospective setting.

We explore the localization of a guest N-myristoylated methyl glycine anchor dipeptide in a phospholipid environment. The dipeptide is part of a conservative sequence, which ensures proper association of a wide group of proteins in living organisms with a cellular phospholipid membrane. Using linear and two-color anharmonic infrared spectroscopy, we measure relative degrees of hydration of the amide I modes of the dipeptide and of phospholipid carbonyls. The atomic density of water in dependence of the distance from the hydrophobic center of the bilayer (a result of an independent Neutron scattering experiment) allows us to determine the relative altitudes of the peptide carbonyls with respect to those of the phospholipid ones. Considering this, and the dimensions of the dipeptide molecular frame, we anticipate the average angle between the backbone of the dipeptide and the normal to the membrane surface. The results provide a descriptive picture of the depth and geometry of partitioning of a guest N-myristoylated methyl glycine anchor dipeptide into a phospholipid membrane.

Being largely driven by electrostatic interactions, hydration compensates hydrophobic repulsion and, thus, contributes decisively in structural expressions of molecules in a phospholipid membrane environment. Here, we explore the nature of the aqueous state associated with carbonyl moieties of a phospholipid bilayer. The task is of an obvious difficulty, since water clustering at a membrane interface implies the presence of various aqueous states giving rise to spectral inhomogeneity. The resultant frequency overlap of the optical response from states of differing nature obscures the structural analysis. We extract the information on water next to phospholipid carbonyls by monitoring the O-D stretch perturbation upon direct infrared excitation of lipid carbonyl groups. Modelling the signal with the help of quantum computations and molecular dynamics simulation, we extract the geometry for the optimal placement of water next to carbonyl moieties, and anticipate the time scale of the water molecule displacement, leading to the disruption of the hydrogen bond, upon direct excitation of the C=O group. The picture we provide here is of general and applied value. The practical importance stems from the necessity of experimentally characterizing the hydration of polar moieties in polypeptides (of pharmacological significance) when in a phospholipid environment, a task not yet achieved.

The solvation dynamics of methyl acetate in heavy water are analyzed by means of two-dimensional infrared spectroscopy, in conjunction with Car-Parrinello molecular dynamics simulations. The C horizontal lineO stretching infrared band of methyl acetate in water splits into a doublet as a consequence of the hydrogen bond interaction with the solvent, which leads to the equilibrium between two solvated species, consisting of one methyl acetate molecule bonded to one and two water molecules. The structure and dynamics of the water molecules bound to methyl acetate are characterized by means of experiments and simulations, allowing an accurate description of the kinetics of the exchange process and the lifetime of the hydrogen bond.

Vibrational dynamics of liquid formamide is studied in the spectral region of the amide I mode by means of linear and two-dimensional infrared spectroscopies. The two-dimensional spectrum has a complex structure to be connected to the partially excitonic nature of the vibrational states. The measurements performed on a 1:10 (12)C:(13)C formamide isotopic mixture allow separating the broadening contribution due to the inhomogeneous frequency distribution of the local oscillators from that of excitonic origin. A model based on the Kubo picture of the line broadening is used, together with the dynamic information obtained from a molecular dynamics simulation, to fit the spectra of the (12)C formamide impurity in the isotopic mixture. The relevant dynamical information, such as the amplitude of the frequency fluctuations, lifetime of the second vibrational excited state, and anharmonicity, is thus recovered. By appropriately combining the outcomes of experiments and molecular dynamics simulation, we demonstrate that motional narrowing determines the line shape of the amide I resonance to a large extent. The same analysis provides an estimate of the transition dipole moment of formamide, which results in good agreement with an ab initio calculation. The calculated frequency fluctuation correlation time is found to be comparable to the hydrogen-bond lifetime, which defines the basic structural relaxation rate of the networked liquid.

We explore the two-dimensional infrared response of D(2)O and of OD impurity at the interface of phospholipid membrane fragments. The spectra of the two aqueous states are inhomogeneously broadened due to the absorption of water molecule associated with the membrane interface in different structural sites. The nonlinear spectra of the two species allow disentangling of the spectral contributions of the aqueous states of two types: where the stretching modes are under effective mixing and where the stretching modes are uncoupled. By reviewing the results of the experimental studies with the support of molecular dynamic simulation we identify the spectral signatures of the main structural motives responsible for the inhomogeneous distribution of resonances in the infrared OD stretching region. Our analysis provides a quantitative estimate of the statistical population of the different aqueous species at the polar interface of the bilayer.

Introduction: Safety issues should always be kept in mind when using diagnostic ultrasound, which is associated with potentially hazardous bio-effects, especially with the introduction of new technologies., Aim: To assess the level of awareness and knowledge of safety issues related to the clinical use of ultrasound among physician-members of the Italian National Society for Ultrasound., Materials and Methods: A questionnaire with 11 multiple-choice questions was sent to members of the Italian Society for Ultrasound in Medicine and Biology. The answers were forwarded from the Society's Secretariat to the investigators, who statistically analyzed the data., Results: The mean age of the 105 respondents was 44 years. The most frequent kind of ultrasound examinations (in addition to conventional B-mode) were: Doppler (74%), contrast-enhanced US (43%), and pediatric studies (43%). Only 50-60% of the responders knew the correct definitions of the terms thermal index and mechanical index. Almost all respondents understood the bio-effects reflected by the thermal index, but only a minority knew the most likely organ target of bio-effects related to the mechanical index and what do indicate the units in which the thermal index is expressed. The majority knew that fetuses are at higher risk of damage. Few respondents were able to identify the correct safety statements included in the recommendations of the International Ultrasound Societies., Conclusion: In conclusion, the present findings indicate that greater efforts of National Ultrasound Societies are warranted in disseminating knowledge of the bio-effects of diagnostic ultrasound modalities among operators.

A series of dendrimeric compounds bearing pyrene units were synthesized to afford light-harvesting antennae based on the formation of intramolecular excimers. The synthetic plan profited from the efficiency of the Huisgen reaction, the 1,3-dipolar cycloaddition of azides and terminal alkynes, which allowed ready assembly of the different building blocks. The three molecular antennae obtained, of increasing generation, revealed efficient energy transfer both in solution and in the solid state.

Purpose: Hepatic hydrothorax is defined as the accumulation of pleural effusion in a cirrhotic patient in the absence of pulmonary or cardiac disease. Peritoneal fluid can pass into the pleural space through diaphragmatic fenestrations. The demonstration of such passage is important to establish the diagnosis of hepatic hydrothorax and can be achieved by intraperitoneal injection of nuclear contrast agents. Our aim was to evaluate the ability of contrast enhanced ultrasound in the detection of peritoneal-pleural communications., Materials and Methods: Seven patients with cirrhotic ascites and pleural effusion were studied in order to make a diagnosis of hepatic hydrothorax. SonoVue was injected into the peritoneal cavity (9.8 mL), and the peritoneal and pleural cavities were monitored by ultrasound. All patients were then studied using a nuclear scan., Results: Passage of SonoVue from the peritoneal to the pleural cavities was seen in 5 patients. In 2 patients, no passage of contrast agent was detectable. Nuclear scan was consistent with contrast enhanced ultrasound in all patients., Conclusion: This study shows that the presence of peritoneal-pleural communications can be demonstrated by real time contrast enhanced ultrasound, whose results are comparable to those of nuclear scan. Contrast enhanced ultrasound is cheaper and could theoretically be performed wherever ultrasound facilities are available.

We have developed a fitting algorithm able to extract spectral and dynamic properties of a three level oscillator from a two-dimensional infrared spectrum (2D-IR) detected in time resolved nonlinear experiments. Such properties go from the frequencies of the ground-to-first and first-to-second vibrational transitions (and hence anharmonicity) to the frequency-fluctuation correlation function. This last is represented through a general expression that allows one to approach the various strategies of modeling proposed in the literature. The model is based on the Kubo picture of stochastic fluctuations of the transition frequency as a result of perturbations by a fluctuating surrounding. To account for the line-shape broadening due to pump pulse spectral width in double-resonance measurements, we supply the fitting algorithm with the option to perform the convolution of the spectral signal with a Lorentzian function in the pump-frequency dimension. The algorithm is tested here on 2D-IR pump-probe spectra of a Gly-Ala dipeptide recorded at various pump-probe delay times. Speedup benchmarks have been performed on a small Beowulf cluster. The program is written in FORTRAN language for both serial and parallel architectures and is available free of charge to the interested reader., ((c) 2008 Wiley Periodicals, Inc.)

The present study aims to understand the dynamical properties of water and OH groups layered on an alumina surface mainly by means of femtosecond IR-pump IR-probe transient absorption spectroscopy. The experimental results obtained demonstrate the existence of several kinds of O-H vibrators on the surface of alumina membranes, distinguishing them by their behavior on the femtosecond time scale and by the anisotropy of their spectral response. In the high-frequency region (>3400 cm-1), the absorption is due to well-packed aluminol groups and to physisorbed water patches on the surface. When pumping at 3200 cm-1, physisorbed water hydrogen-bonded to AlOH2+ groups is observed. The anisotropy measurements demonstrate the existence of an efficient energy-transfer mechanism among the water molecules characterized by a time constant of 400 +/- 100 fs. The persisting anisotropy at long times, especially in the case of AlOH groups and of the structured physisorbed water layer on top of them, proves the anisotropic structuring induced by the surface. The excitation at 3000 cm-1 enables the detection of a photon-induced proton-transfer reaction. The proton back-transfer reaction time constant is 350 +/- 50 fs. From anisotropy measurements, we estimate the proton hopping time to be 900 +/- 100 fs in a locally extended water network lying on the surface.