Diastereo- and Enantioselective Construction of Stereochemical Arrays Exploiting Non-Classical Hydrogen Bonding in Enolborates.

We report a copper-catalyzed reductive aldol addition to aldehydes and ketones, with pinacolborane as stoichiometric reductant, that results in the generation of stereodefined syn-aldol products.  Cyclic, acyclic, fused and spirocyclic aldols bearing contiguous stereocenters are obtained with excellent yields and diastereoselectivities.  Moreover, enantioselective reactions could be carried out with cycloalkenones to deliver aldols bearing three contiguous stereocenters and with up to 98% ee.  Computations reveal that the enolborate intermediate undergoes the syn-aldol reaction via a twist-boat transition state that is stabilized by non-classical hydrogen bonding interactions.

Dearomative Intramolecular (4+3) Cycloadditions of Thiophenes.

Unexpectedly facile dearomative intramolecular (4+3) cycloadditions of thiophenes with epoxy enolsilanes, providing sulfur-bridged cycloadducts, are reported. A total of fifteen thiophene substrates have been found to undergo (4+3) cycloaddition smoothly to produce endo and exo (4+3) adducts in yields of up to 83% with moderate to good diastereoselectivity. Complete conservation of enantiomeric purity was observed when the optically enriched epoxide was used. The desulfurizing transformations of the sulfur-bridged skeleton of the cycloadducts provide functionalized 6,7-fused bicyclic frameworks consisting of 1,3-cycloheptadiene subunits. Density functional theory calculations reveal the origins of the facile dearomatization of thiophenes in these (4+3) cycloadditions.

Controlled Living Cascade Polymerization of Polycyclic Enyne Monomers: Leveraging Complete Degradability for a Stereochemical and Structural Investigation.

Cascade polymerizations recently gained significant attention due to their use of unique transformations, involving multiple bond making and/or breaking steps, when converting monomers to repeat units. However, designing complex cascade polymerizations which proceed in a controlled manner is very challenging. Various side reactions can hamper polymerization performance and the efficiency of the cascade. In this work, we explore a metathesis-based cascade polymerization of unique polycyclic enyne monomers, which contain a terminal alkyne and two cyclic alkenes. By modifying the monomer's stereochemistry, linkers, and ring types, we were able to modulate the polymerization performance and the extent to which a complete cascade reaction occurs. Upon subjecting the resulting polymers to mild acidic conditions and analyzing the degradation products, we were able to calculate the percentage of repeat units derived from a complete cascade reaction (termed the cascade efficiency). In addition to identifying how various structural parameters in the monomer influence the success of a cascade polymerization, we were able to achieve controlled living cascade polymerizations of multiple monomers with >99% cascade efficiency and produce various block copolymers.

Pathological examination of breast cancer samples before and after neoadjuvant therapy: recommendations from the Italian Group for the Study of Breast Pathology - Italian Society of Pathology (GIPaM-SIAPeC).

Neoadjuvant therapy (NAT) in breast cancer is administered to downstage the tumor, de-escalate surgery, and provide prognostic information that can be used to tailor subsequent adjuvant therapy. In this respect, the pathological evaluation of both pre-NAT biopsies and post-NAT surgical specimens is crucial to precisely assess the treatment response. With the increasing possibilities of NAT protocols and the rising number of eligible patients, it has become extremely important to standardize the pathological response assessment. Here, we provide an update on the recommendations of the Italian Group for the Study of Breast Pathology - the Italian Society of Pathology (GIPaM-SIAPeC) for the analysis of breast cancer samples before and after NAT.

Sugar-Based Polymers from d-Xylose: Living Cascade Polymerization, Tunable Degradation, and Small Molecule Release.

Enyne monomers derived from D-xylose underwent living cascade polymerizations to prepare new polymers with a ring-opened sugar and degradable linkage incorporated into every repeat unit of the backbone. Polymerizations were well-controlled and had living character, which enabled the preparation of high molecular weight polymers with narrow molecular weight dispersity values and a block copolymer. By tuning the type of acid-sensitive linkage (hemi-aminal ether, acetal, or ether functional groups), we could change the degradation profile of the polymer and the identity of the resulting degradation products. For instance, the large difference in degradation rates between hemi-aminal ether and ether-based polymers enabled the sequential degradation of a block copolymer. Furthermore, we exploited the generation of furan-based degradation products, from an acetal-based polymer, to achieve the release of covalently bound reporter molecules upon degradation.

Biomimetic Approach Toward Enterocin and Deoxyenterocin.

Enterocin (vulgamycin) is a structurally remarkable natural product with significant antibiotic activity. The synthesis of a linear polyketide resembling a biosynthetic precursor was achieved using an unusual acyloin reaction. A diazo group was introduced as a protecting group for an enolizable ketone. We were unable to bring about the envisioned biomimetic aldol addition cascade and gained insights into the feasibility of this process by DFT calculations. As an alternative approach to enterocin, we developed a Cu-catalyzed intramolecular cyclopropanation followed by a MgI2-induced fragmentation to install the 2-oxabicyclo[3.3.1]nonane core of the natural product.

ALLiance for sEcondary PREvention after an acute coronary syndrome. The ALLEPRE trial: A multicenter fully nurse-coordinated intensive intervention program.

The main objective of cardiovascular disease prevention is to reduce morbidity and mortality by promoting a healthy lifestyle, reducing risk factors, and improving adherence to medications. Secondary prevention after an acute coronary syndrome has proved to be effective in reducing new cardiovascular events, but its limited use in everyday clinical practice suggests that there is considerable room for improvement. The short-term results of evidence-based studies of nurse-coordinated secondary prevention programs have been positive, but there is a lack of long-term outcome data. The Alliance for the Secondary Prevention of Cardiovascular Disease in the Emilia-Romagna region (ALLEPRE) is a multicenter, randomized, controlled trial designed to compare the effects of a structured nurse-coordinated intensive intervention on long-term outcomes and risk profiles after an acute coronary syndrome with those of the standard of care. All of the patients randomized to the intervention group take part in 9 one-to-one sessions with an experienced nurse from the participating centers with the aim at promoting healthy lifestyles, reducing risk factors, and increasing adherence to medication over a mean period of 5 years. The primary clinical end point is the reduction in the risk of the 5-year occurrence of major adverse events (a composite of cardiovascular mortality, nonfatal reinfarction, and nonfatal stroke). The primary surrogate end point is the achievement of prespecified targets relating to classical risk factors, lifestyle modifications, and adherence to pharmacological therapy after 2 years of follow-up. Coronary heart disease is a chronic degenerative disease, and patients who recover from an acute coronary syndrome (ACS) are at high risk of developing recurrent events.1 Although secondary prevention measures have proved to be effective and are strongly recommended by all of the international guidelines,2., 3. the 4 EUROASPIRE surveys4., 5., 6., 7., 8. showed that there was still a high prevalence of conventional risk factors, that secondary prevention measures were inadequately implemented, and that their main goals were often not reached. In addition, there were considerable discrepancy in secondary prevention practices between centers and countries, and a widespread underuse of cardiac prevention and rehabilitation programs despite their demonstrated effectiveness in reducing cardiovascular risk over time.9., 10. Over the last 10 years, nurses have been increasingly involved in successful cardiovascular risk management,11., 12., 13. but although this has improved levels of cardiovascular risk, no clear reduction in hard end points such as major cardiovascular adverse events and mortality has been demonstrated.10 The aim of the ALLEPRE trial is to evaluate the benefit of a homogeneous, structured, secondary prevention intervention program, fully coordinated by nurses from in- and outpatient clinics, in terms of cardiovascular risk profiles and major clinical events in ACS patients living in the large Emilia-Romagna region of Italy.

A QM/MM and QM/QM/MM study of Kerr, Cotton-Mouton and Jones linear birefringences in liquid acetonitrile.

QM/MM and QM/QM/MM protocols are applied to the ab initio study of the three linear birefringences Kerr, Cotton-Mouton, and Jones, as shown by acetonitrile in the gas and pure liquid phases. The relevant first-order properties as well as linear, quadratic, and cubic frequency-dependent response functions were computed using time-dependent Kohn-Sham density-functional theory with use of the standard CAM-B3LYP functional. In the liquid phase, a series of room temperature (293.15 K) molecular dynamics snapshots were selected, for which averaged values of the observables were obtained at an optical wavelength of 632.8 nm. The birefringences were computed for electric and magnetic induction fields corresponding to the laboratory setup previously employed by T. Roth and G. L. J. A. Rikken in Phys. Rev. Lett., 2000, 85, 4478. Under these conditions, acetonitrile is shown to exhibit a weak Jones response-in fact roughly 6.5 times smaller than the limit of detection of the apparatus employed in the measurements mentioned above. A comparison is made with the corresponding gas-phase results and an assessment is made of the index of measurability, estimating the degree of overlap of the three birefringences in actual measurements. For acetonitrile, it is shown that this index is a factor of 3.6 and 6.7 larger than that of methylcyclopentadienyl-Mn-tricarbonyl and cyclohexadienyl-Fe-tricarbonyl, respectively-two compounds reported in Phys. Rev. Lett., 2000, 85, 4478 to exhibit a strong Jones signal.

Predicting the Helical Sense of Poly(phenylacetylene)s from their Electron Circular Dichroism Spectra.

The calculated ECD spectrum (time-dependent density functional theory TD-DFT) for small oligomers of polyphenylacetylenes (PPAs) show a very good match with the experimental spectra of the PPA polymers, particularly with the first Cotton band associated to the helical sense of the internal polyenic backbone. This has been proven with a series of PPAs representative of cis-cisoidal, cis-transoidal, compressed and stretched polyene backbones, with identical or opposite internal/external rotational senses and allows the prediction of the helical sense of the internal helix of a PPA directly from its CD spectra.

Digital breast tomosynthesis (DBT): recommendations from the Italian College of Breast Radiologists (ICBR) by the Italian Society of Medical Radiology (SIRM) and the Italian Group for Mammography Screening (GISMa).

This position paper, issued by ICBR/SIRM and GISMa, summarizes the evidence on DBT and provides recommendations for its use. In the screening setting, DBT in adjunct to digital mammography (DM) increased detection rate by 0.5-2.7‰ and decreased false positives by 0.8-3.6% compared to DM alone in observational and double-testing experimental studies. The reduction in recall rate could be less prominent in those screening programs which already have low recall rates with DM. The increase in radiation exposure associated with DM/DBT protocols has been solved by the introduction of synthetic mammograms (sDM) reconstructed from DBT datasets. Thus, whenever possible, sDM/DBT should be preferred to DM/DBT. However, before introducing DBT as a routine screening tool for average-risk women, we should wait for the results of randomized controlled trials and for a statistically significant and clinically relevant reduction in the interval cancer rate, hopefully associated with a reduction in the advanced cancer rate. Otherwise, a potential for overdiagnosis and overtreatment cannot be excluded. Studies exploring this issue are ongoing. Screening of women at intermediate risk should follow the same recommendations, with particular protocols for women with previous BC history. In high-risk women, if mammography is performed as an adjunct to MRI or in the case of MRI contraindications, sDM/DBT protocols are suggested. Evidence exists in favor of DBT usage in women with clinical symptoms/signs and asymptomatic women with screen-detected findings recalled for work-up. The possibility to perform needle biopsy or localization under DBT guidance should be offered when DBT-only findings need characterization or surgery.

Origin-independent two-photon circular dichroism calculations in coupled cluster theory.

We present the first origin-independent approach for the treatment of two-photon circular dichroism (TPCD) using coupled cluster methods. The approach is assessed concerning its behavior on the choice of the basis set and different coupled cluster methods. We also provide a comparison of results from CC2 with those from density functional theory using the CAM-B3LYP functional. Concerning the basis set we note that in most cases an augmented triple zeta basis or a doubly augmented double zeta basis is needed for reasonably converged results. In the comparison of different coupled cluster methods results from CCSD, CC3 and CC2 have been found to be quite similar in most cases, while CCS results differ remarkably from the results at the higher levels. However, this proof-of-principle study also shows that further benchmarking of DFT and CC2 against accurate coupled cluster reference values (e.g. CCSD or CC3) is needed.

Ab initio study of the enantio-selective magnetic-field-induced second harmonic generation in chiral molecules.

We present a systematic ab initio study of enantio-selective magnetic-field-induced second harmonic generation (MFISHG) on a set of chiral systems ((l)-alanine, (l)-arginine and (l)-cysteine; 3,4-dehydro-(l)-proline; (S)-α-phellandrene; (R,S)- and (S,S)-cystine disulphide; N-(4-nitrophenyl)-(S)-prolinol, N-(4-(2-nitrovinyl)-phenyl)-(S)-prolinol, N-(4-tricyanovinyl-phenyl)-(S)-prolinol, (R)-BINOL, (S)-BINAM and 6-(M)-helicene). The needed electronic frequency dependent cubic response calculations are performed within a density functional theory (DFT) approach. A study of the dependence of the property on the choice of electron correlation, on one-electron basis set extension and on the choice of magnetic gauge origin is carried out on a prototype system (twisted oxygen peroxide). The magnetic gauge dependence analysis is extended also to the molecules of the set. An attempt to analyze the structure-property relationships is also made, based on the results obtained for biphenyl (in a frozen twisted conformation), for prolinol and for some of their derivatives. The strength of the effect is discussed, in order to establish its measurability with a proposed experimental setup.

Theoretical investigation of the broad one-photon absorption line-shape of a flexible symmetric carbazole derivative.

The one-photon absorption spectrum of a carbazole derivative has been studied by employing density functional response theory combined with a mixed quantum/classical (QC) approach to simulate the spectral shape. In a first step of our analysis we employed the vertical gradient (VG) vibronic model to investigate the role of Franck-Condon (FC) profiles of the first ten electronic excited states of the system, underlying most of the range of the experimental spectrum. We then focussed on the first six excited states covering the low-energy region of the spectrum, and investigated the effect of inter-state electronic couplings on the spectral shapes within Herzberg-Teller (HT) theory. Furthermore, in order to introduce the broadening effects due to the two inter-ring torsions, we employed a QC approach, adopting VG vibronic models for high-frequency modes and computing the contribution of the torsions to the spectrum from the distribution of the excitation energies along a two-dimensional relaxed potential energy. Finally, we estimated the solvent inhomogeneous broadening by computing the solvent reorganization energy using a polarizable continuum model. Our calculations allow us to obtain a non-phenomenological description of the low-energy part of the spectrum in semi-quantitative agreement with experiment and to dissect the relative importance of solvent, torsional flexibility, FC vibronic progressions, and inter-state couplings in determining its broad spectral shapes and the modulation of its intensity. Our analysis also clearly highlights that the investigated carbazole represents a big challenge for available methodologies due to the existence of many close-lying excited electronic states coupled by internal low-frequency and high-frequency motions and by solvent fluctuations. The study of their impact on the spectra at the HT level is only approximate and more refined treatments would require a fully quantum-dynamical calculation on the manifold of the coupled states.

A complex-polarization-propagator protocol for magneto-chiral axial dichroism and birefringence dispersion.

A computational protocol for magneto-chiral dichroism and magneto-chiral birefringence dispersion is presented within the framework of damped response theory, also known as complex polarization propagator theory, at the level of time-dependent Hartree-Fock and time-dependent density functional theory. Magneto-chiral dichroism and magneto-chiral birefringence spectra in the (resonant) frequency region below the first ionization threshold of R-methyloxirane and l-alanine are presented and compared with the corresponding results obtained for both the electronic circular dichroism and the magnetic circular dichroism. The additional information content yielded by the magneto-chiral phenomena, as well as their potential experimental detectability for the selected species, is discussed.

Recommendations for breast imaging follow-up of women with a previous history of breast cancer: position paper from the Italian Group for Mammography Screening (GISMa) and the Italian College of Breast Radiologists (ICBR) by SIRM.

Women who were previously treated for breast cancer (BC) are an important particular subgroup of women at intermediate BC risk. Their breast follow-up should be planned taking in consideration a 1.0-1.5 % annual rate of loco-regional recurrences and new ipsilateral or contralateral BCs during 15-20 years, and be based on a regional/district invitation system. This activity should be carried out by a Department of Radiology integrating screening and diagnostics in the context of a Breast Unit. We recommend the adoption of protocols dedicated to women previously treated for BC, with a clear definition of responsibilities, methods for invitation, site(s) of visits, methods for clinical and radiological evaluation, follow-up duration, role and function of family doctors and specialists. These women will be invited to get a mammogram in dedicated sessions starting from the year after the end of treatment. The planned follow-up duration will be at least 10 years and will be defined on the basis of patient's age and preferences, taking into consideration organizational matters. Special agreements can be defined in the case of women who have their follow-up planned at other qualified centers. Dedicated screening sessions should include: evaluation of familial/personal history (if previously not done) for identifying high-risk conditions which could indicate a different screening strategy; immediate evaluation of mammograms by one or, when possible, two breast radiologists with possible addition of supplemental mammographic views, digital breast tomosynthesis, clinical breast examination, breast ultrasound; and prompt planning of possible further workup. Results of these screening sessions should be set apart from those of general female population screening and presented in dedicated reports. The following research issues are suggested: further risk stratification and effectiveness of follow-up protocols differentiated also for BC pathologic subtype and molecular classification, and evaluation of different models of survivorship care, also in terms of cost-effectiveness.

A Combined Experimental-Computational Investigation to Uncover the Puzzling (Chiro-)optical Response of Pyridocyclophanes: One- and Two-Photon Spectra.

A combined experimental-computational analysis of the one- and two-photon absorption (OPA, TPA) and the electronic circular dichroism (ECD) of complex chiral shape-persistent (2,6)-pyrido[142 ]allenoacetylenic cyclophane, (P,P,P,P)-MC[142 ] enantiomers, sheds light on the origin of their peculiar spectral signatures. The study on MC[142 ], which is represented in solution by three possible conformers, indicates that two of them (chair and twist) are the prevalent conformers at room temperature; the population ratio depending on the solvent. The complex shape of the red-edge of the UV and ECD spectra is qualitatively reproduced by using vibronic calculations and assigned to progressions on the ethynyl stretchings observable only in the chair and twist conformers. The picture arising from the analysis of the linear spectra is confirmed by two-photon spectroscopies, showing that they constitute valuable tools for the exploration of high-energy electronic transitions in pyridoallenoacetylenic cyclophanes. Discrepancies among computed and experimental spectra point out that an accurate description of such complex systems with a large delocalized π framework and a dense manifold of electronic excited state remains a challenge for theoretical models.

A computational protocol for the study of circularly polarized phosphorescence and circular dichroism in spin-forbidden absorption.

We present a computational methodology to calculate the intensity of circular dichroism (CD) in spin-forbidden absorption and of circularly polarized phosphorescence (CPP) signals, a manifestation of the optical activity of the triplet-singlet transitions in chiral compounds. The protocol is based on the response function formalism and is implemented at the level of time-dependent density functional theory. It has been employed to calculate the spin-forbidden circular dichroism and circularly polarized phosphorescence signals of valence n → π* and n ← π* transitions, respectively, in several chiral enones and diketones. Basis set effects in the length and velocity gauge formulations have been explored, and the accuracy achieved when employing approximate (mean-field and effective nuclear charge) spin-orbit operators has been investigated. CPP is shown to be a sensitive probe of the triplet excited state structure. In many cases the sign of the spin-forbidden CD and CPP signals are opposite. For the ß,γ-enones under investigation, where there are two minima on the lowest triplet excited state potential energy surface, each minimum exhibits a CPP signal of a different sign.

Circular and linear magnetic birefringences in xenon at λ = 1064 nm.

The circular and linear magnetic birefringences corresponding to the Faraday and the Cotton-Mouton effects, respectively, have been measured in xenon at λ = 1064 nm. The experimental setup is based on time dependent magnetic fields and a high finesse Fabry-Pérot cavity. Our value of the Faraday effect is the first measurement at this wavelength. It is compared to theoretical predictions. Our uncertainty of a few percent yields an agreement at better than 1σ with the computational estimate when relativistic effects are taken into account. Concerning the Cotton-Mouton effect, our measurement, the second ever published at λ = 1064 nm, agrees at better than 1σ with theoretical predictions. We also compare our error budget with that established for other experimental published values.

Azabicycles construction: the transannular ring contraction with N-protected nucleophiles.

Synthetic strategies are one of the most critical factors for the success of a synthetic campaign, but most importantly they are crucial for the economy and the efficiency of the sequence. Within this perspective, the synthesis of azabicyclic scaffolds, constituents of many bioactive alkaloids, can be tackled using tandem transannular ring contractions-protecting group cleavages. Commonly these reactions feature medium-sized cyclic N-protected amines that carry a potential electrophilic site. Under the correct conditions this site is activated, and the protecting group is fragmented, inducing a transannular reaction. For the first time, we review in detail this strategy's applications, which span from the assembly of small molecules to complex molecular architectures.

On the origin of the very strong two-photon activity of squaraine dyes--a standard/damped response theory study.

In the present work, we report the mechanism of a very large increase in the two-photon (TP) activity of squaraine based molecules upon changing the substituents. The replacement of a specific fused ring by ethylene or ethyne moieties enhances the TP transition strength of these molecules up to the order of 10(13) au (∼10(10) GM), both in the gas phase as well as in dichloromethane solvent. Our calculations decisively establish that the reason for this large enhancement in the TP activity of the studied systems is the severe decrease in the corresponding detuning energies. We explain this fact using damped response theory calculations and provide a novel design strategy to control the detuning energy of such molecules. The results are benchmarked against the available experimental findings.