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The process in which locally confined epithelial malignancies progressively evolve into invasive cancers is often promoted by unjamming, a phase transition from a solid-like to a liquid-like state, which occurs in various tissues. Whether this tissue-level mechanical transition impacts phenotypes during carcinoma progression remains unclear. Here we report that the large fluctuations in cell density that accompany unjamming result in repeated mechanical deformations of cells and nuclei. This triggers a cellular mechano-protective mechanism involving an increase in nuclear size and rigidity, heterochromatin redistribution and remodelling of the perinuclear actin architecture into actin rings. The chronic strains and stresses associated with unjamming together with the reduction of Lamin B1 levels eventually result in DNA damage and nuclear envelope ruptures, with the release of cytosolic DNA that activates a cGAS-STING (cyclic GMP-AMP synthase-signalling adaptor stimulator of interferon genes)-dependent cytosolic DNA response gene program. This mechanically driven transcriptional rewiring ultimately alters the cell state, with the emergence of malignant traits, including epithelial-to-mesenchymal plasticity phenotypes and chemoresistance in invasive breast carcinoma.

In the version of this article initially published, the first name of Flora Ascione was listed as “Floriana”; the error has been corrected in the HTML and PDF versions of the article.

Purpose: Monoallelic germ-line mutations in the BRCA1/FANCS, BRCA2/FANCD1 and PALB2/FANCN genes confer high risk of breast cancer. Biallelic mutations in these genes cause Fanconi anemia (FA), characterized by malformations, bone marrow failure, chromosome fragility, and cancer predisposition (BRCA2/FANCD1 and PALB2/FANCN), or an FA-like disease presenting a phenotype similar to FA but without bone marrow failure (BRCA1/FANCS). FANCM monoallelic mutations have been reported as moderate risk factors for breast cancer, but there are no reports of any clinical phenotype observed in carriers of biallelic mutations.& para;& para;Methods: Breast cancer probands were subjected to mutation analysis by sequencing gene panels or testing DNA damage response genes.& para;& para;Results: Five cases homozygous for FANCM loss-of-function mutations were identified. They show a heterogeneous phenotype including cancer predisposition, toxicity to chemotherapy, early menopause, and possibly chromosome fragility. Phenotype severity might correlate with mutation position in the gene.& para;& para;Conclusion: Our data indicate that biallelic FANCM mutations do not cause classical FA, providing proof that FANCM is not a canonical FA gene. Moreover, our observations support previous findings suggesting that FANCM is a breast cancer-predisposing gene. Mutation testing of FANCM might be considered for individuals with the above-described clinical features.

Dislocation-density-related equations were proved to be promising tools to correlate tensile plastic behaviour and microstructure in ductile irons (DIs), revealing distinct relationships between equation parameters and microstructure features in austempered ductile irons (ADI) and isothermed ductile irons (IDI). These equations resulted to be successful also in the characterization of the austempering process through the plastic behaviour analysis of tensile tests of an ADI 1050 that was quenched at different times during austempering. The equation parameters could indeed be correlated to the time window for the best ausferrite, and could predict the precipitation of the deleterious epsilon' carbides for long austempering times. In the present work the results of the tensile plastic behaviour analysis of different DIs through dislocation-density-related equations are reported. The aim of the analysis was to test the capability of these equations to assess the microstructure quality of DIs and support their industrial production.

È stata studiata la capacità di un'equazione costitutiva, caratterizzata da parametri fisici, di correlare il comportamento plastico con la microstruttura di un ghisa sferoidale austemperata (ADI), allo scopo di valutare la stabilità della austenite residua durante austempering ed ottenere la microstruttura ausferritica ottimale. La finestra temporale critica per interrompere la reazione è quella in cui la trasformazione di austempering è giunta a saturazione producendo una frazione austenitica caratterizzata dalla massima possibile stabilità, prima che inizi il secondo stadio caratterizzato dalla precipitazione dei carburi ??'. La ghisa sferoidale ADI 1050 è stata, quindi, temprata in momenti diversi durante austempering ed i campioni così ottenuti sono stati deformati mediante prove di trazione a temperatura ambiente. I campioni testati in trazione hanno presentato un andamento dei carichi Rm e degli allungamenti a rottura eR coerenti con la microstruttura osservata, manifestando per tempi di austempering molto elevati una significativa riduzione di duttilità attribuibile alla precipitazione della fase infragilente ??', come riportato in letteratura. Gli andamenti dei dati Rm e eR in funzione dei tempi di austempering hanno però presentato un'ampia dispersione, cosicché non è stato possibile individuare univocamente la finestra ottimale della trasformazione per bloccare la trasformazione. Per questo motivo, le curve di trazione sono state interpolate con una equazione costitutiva avente parametri fisici, basati sulla descrizione e l'evoluzione della microstruttura del materiale. Questi parametri hanno presentato una minore dispersione ed un andamento regolare in funzione dei tempi di austempering, permettendo quindi di determinare la finestra critica per interrompere il processo industriale di austempering.

La ghisa sferoidale ADI 1050 è stata temprata in momenti diversi durante il processo di austempering ed i campioni così ottenuti sono stati deformati mediante prove di trazione a temperatura ambiente. A seconda del tempo al quale il materiale è stato temprato, la microstruttura dei campioni ADI, osservata mediante metallografia ottica convenzionale, ha presentato martensite + ferrite + austenite metastabile per tempi di austempering ridotti, quando la reazione di austempering non era ancora esaurita. Per tempi più elevati, la microstruttura è risultata essere completamente ferritica + austenitica, il che rappresenta la struttura ausferritica ottimale. I campioni testati in trazione hanno presentato un andamento dei carichi massimi Rm e degli allungamenti a rottura eR coerenti con la microstruttura osservata, manifestando però per tempi di austempering molto elevati una significativa riduzione di duttilità, attribuibile alla precipitazione della fase infragilente epsilon', come riportato in letteratura. Il tempo più idoneo per interrompere la reazione è infatti quello in cui la trasformazione di austempering si è esaurita, prima però che la precipitazione epsilon' avvenga. Purtroppo gli andamenti dei dati Rm e eR hanno presentato un'ampia dispersione, cosicché non è stato possibile individuare univocamente un intervallo critico di tempi per ottenere l'ausferrite ottimale. Dunque, le curve di trazione sono state interpolate prima con equazioni costitutive empiriche e poi con equazioni aventi parametri fisici direttamente correlabili alla microstruttura del materiale, parametri quali la densità dislocativa ed il libero cammino medio (lambda) delle dislocazioni, con l'obiettivo di determinare in maniera precisa l'intervallo di tempo opportuno per interrompere il processo industriale di austempering e quindi ottenere la microstruttura ausferritica ottimale. Le equazioni empiriche hanno fallito in questo obiettivo, mentre le equazioni con parametri fisici hanno avuto successo. In particolare, il parametro lambda ottenuto mediante modellizzazione delle curve di flusso plastico con l'equazione di Estrin ha presentato un andamento regolare con un ridotta diffusione, tanto che è stato possibile trovare un ampio massimo in corrispondenza di uno specifico intervallo di tempo di austempering. Questo massimo è stato associato alle condizioni di ausferrite ottimale ed il corrispondente intervallo di tempo alla finestra critica per cui interrompere il processo di austempering

[object Object]An unprecedented technique for the in situ generation of indolyl ortho-quinodimethanes from 2- methylindole-based methylenemalononitriles by aminemediated remote C(sp3)¢H deprotonation was developed. These intermediates were efficiently trapped by diverse enals to provide a rapid entry to 2,9-dihydro-1H-carbazole- 3-carboxyaldehyde structures through a formal asymmetric [4+2] eliminative cycloaddition governed by a a,adiphenylprolinol trimethylsilyl ether catalyst.

A direct aminocatalytic synthesis has been developed for the chemo-, regio-, diastereo-, and enantioselective construction of densely substituted polycyclic carbaldehydes containing fused cyclohexadiene rings. The chemistry utilizes, for the first time, remotely enolizable ?-extended allylidenemalononitriles as electron-rich 1,3-diene precursors in a direct eliminative [4+2] cycloaddition with both aromatic and aliphatic ?,?-unsaturated aldehydes. The generality of the process is demonstrated by approaching 6,6-, 5,6-, 7,6-, 6,6,6-, and 6,5,6-fused ring systems, as well as biorelevant steroid-like 6,6,6,6,5- and 6,6,6,5,6-rings. A stepwise reaction mechanism for the key [4+2] addition is proposed as a domino bis-vinylogous Michael/Michael/retro-Michael reaction cascade. The utility of the malononitrile moiety as traceless activating group of the dicyano nucleophilic substrates is demonstrated. Without a trace: The covalent activation of ?,?-unsaturated aldehydes with malononitrile produced remotely enolizable ?-extended allylidene malononitriles. Their amine-catalyzed eliminative [4+2] cycloaddition to aromatic and aliphatic enals enabled the construction of cyclohexadiene-containing polycycles with outstanding diastereo- and enantioselectivities. The essential role of the malononitrile handle as a traceless activating moiety was demonstrated.

Objective The aim of the study was to identify efficient PubMed search strategies to retrieve articles regarding putative occupational determinants of farmers’ diseases. Methods Based on Medical Subject Heading (MeSH) definitions and expert knowledge, we selected the MeSH term agricultural workers’ disease and, as candidate search terms, five MeSH terms describing farm work (pesticides, agriculture, rural population, rural health, agrochemicals NOT pesticides) alongside 25 other promising terms. Using random samples of abstracts retrieved by each term, we estimated propor- tions of articles containing potentially pertinent information regarding occupational aetiology in order to formulate two search strategies (one more ‘‘specific’’, one more ‘‘sen- sitive’’). We applied these strategies to retrieve information on possible occupational aetiology among farmers of knee osteoarthritis, multiple sclerosis and kidney cancer. We evaluated the number of abstracts needed to read (NNR) to identify one potentially pertinent article in the context of these pathologies. Results The more ‘‘specific’’ search string was based on the combina- tion of terms that yielded the highest proportion (40%) of potentially pertinent abstracts. The more ‘‘sensitive’’ string was based on use of broader search fields and additional coverage provided by other search terms under study. Using the specific string, the NNR to find one potentially pertinent article were: 1.3 for knee osteoarthritis; 1.3 for multiple sclerosis; 1.1 for kidney cancer. Using the sensitive strategy, the NNR were 1.8, 2.4 and 1.4, respectively. Conclusions The proposed strings could help health care professionals explore putative occupational aetiology for farmers’ diseases (even if not generally thought to be work-related).

La prima edizione delle Linee Guida SIMLII sul rischio associato alla movimentazione manuale di carichi è stata pubblicata nel maggio 2004. Da allora sia in campo scientifico che legislativo si sono verificate numerose novità che hanno imposto una nuova edizione delle Linee Guida stesse. La movimentazione manuale di carichi è un compito lavorativo (e non) che può essere associato a un rischio per la salute (a causa di un possibile sovraccarico biomeccanico) e di questo un medico del lavoro dovrebbe comunque occuparsi, indipendentemente dall’eventuale esistenza di specifici obblighi normativi.

Highly direct, modular syntheses of several natural 8,4¢-oxyneolignans [(-)-1, (+)-1, (-)-2, and (-)-3] and some related variants [(-)-26, (+)-26, (+)-27, and (-)-28] are reported. Utilizing (S)- or (R)-methyl lactate as the chiral sources, two complementary syn- or anti-oriented routes were designed, encompassing nine and five steps, which were carried out to deliver the targets in an enantiomerically pure form. The embodiment of the two independent aryl and aryloxy moieties onto the lactate frame was performed according to a diversity-oriented protocol from the common precursors, aldehydes 6 and ent-6 for the syn-oriented routes and mesyl esters 19 and ent-19 for the anti-oriented routes. These syntheses set the stage for the generation of a wide and diverse repertoire of 8,4¢-oxyneolignan compounds and the broad biological interrogation of its members.

Cost competitive machining of ADI after heat treatment has been a normal practice for about twenty years. In order to be successful with machining after austempering all the metallurgical processes, both in the liquid and solid states, must be carried out at the best level of available technologies, involving all necessary investments to ensure consistent and reproducible quality. A high nodule count and a narrow range of hardness are the first indexes to be monitored. This will ensure the safety of the casting design. Research programs on material properties and material design, together with the success of running applications, are increasingly indicative of the high potential of ADI as a benchmark material for engineering applications. Metallurgical processes applied to castings are based on the unique relationship of spheroidal grade and silicon. This relationship allows us to produce the intermediate structure in austempered cast irons, knows as “Ausferrite”. When compared with steels, ADI castings are less dense, less likely to crack and have excellent wear resistance. Being a multi-phase, high performance material, ADI’s process window is narrower than other conventional materials. For this reason, ADI processes require large investments in the foundry and heat treatment, with maximum integration between engineering design and machining operations.

Efficient, total syntheses of novel 2-deoxy-2-amino-5a-carba-beta-L-mannopyranuronic acid (1) and 2-deoxy-2-amino-5a-carba-beta-L-mannopyranose (2), a positional stereoisomer of validamine, have been achieved in 28% and 24% overall yields and in 12 steps and 13 steps, respectively, from 2-[(tertbutyldimethylsilyl) oxy]furan (3) and (2S)-2,3-O-isopropylideneglyceraldehyde N-benzyl imine (4) via two highly diastereoselective Mukaiyama aldol-related chemical maneuvers. The strategy, which furnishes the targeted carbasugars in enantiopure forms, allows for complete control of the configuration at all five contiguous stereocenters of the targets by utilizing the sole element of chirality present in the aldimine progenitor 4.

The feasibility of the sequential vinylogous aldol (intermolecular)/silylative aldol (intramolecular) addition reactions involving furan- and pyrrole-based dienoxysilanes, 6 and 12, in the synthesis of carbasugar frameworks is illustrated by the preparation of the scantily investigated carbaseptanose and carbaoctanose representatives of this class of compounds. The target compounds, 1, 2, 3, ent-2, ent-3, and 4, were obtained from readily available carbohydrate precursors (5 and 19) in yields of 21-30% over 8-12 steps. The irreversible silylative ring-closing aldolisation of ƒ×-substituted dihydro-5H-furan-2-one and pyrrolidin-2-one aldehydes (9, 16, ent-16, and 22) driven by the TBSOTf/Pri2EtN Lewis acid-Lewis base couple was shown to be a practical, diastereoselective manoeuvre to forge the densely functionalised, medium-sized core carbocycles.

A chiral, divergent synthesis of two carbafuranosylamines, 1 and 2, two carbapyranosylamines, 3 and 4, two carbafuranosylamino acids, 5 and 6, and two carbapyranosylamino acids, 7 and 8, has been achieved. Highlights of the procedure include: a diastereoselective crossed vinylogous Mukaiyama aldol coupling between N-(tert-butoxycarbonyl)-2-ƒË(tert-butyldimethylsilyl)oxyƒÍpyrrole (TBSOP, 9) and 2,3-O-isopropylidene-D-glyceraldehyde (10) for the assembly of the target compound carbon backbone; a high yielding silylative cyclo-aldolization which gives the cyclopentanoid and cyclohexanoid motifs; and a reductive or hydrolytic breakage of the lactam C(O)¡VN link to liberate the carbasugar and install the desired pseudo-anomeric amine and the hydroxymethyl or carboxyl functionalities. The sequences leading to trans-configured carbafuranosyl compounds 1 and 5 and carbapyranosyl compounds 3 and 7 were 12 and 13 step processes, with overall yields of 34%, 35%, 17% and 16%. Cis-configured isomers 2, 4, 6, and 8 were obtained only in minor yields.

Background It has been suggested that withdrawal of inhaled corticosteroids (ICS) in COPD patients on maintenance treatment results in deterioration of symptoms, lung function and exacerbations. The aim of this real-life, prospective, multicentric study was to investigate whether withdrawal of ICS in COPD patients at low risk of exacerbation is linked to a deterioration in lung function and symptoms and to a higher frequency of exacerbations. Methods 914 COPD patients, on maintenance therapy with bronchodilators and ICS, FEV1>50% predicted, and

The silyloxy diene-based construction of carbasugars, previously exploited for the synthesis of four carbocyclic furanose and pyranose analogues, has been investigated further. By introducing a novel silylative cycloaldolization protocol and by adjusting a couple of minor transformations, the efficiency of this synthetic sequence was greatly improved. Through a series of lactone/thiolactone aldehyde cyclization precursors, four carbafuranoses (4a-carba-beta-D-xylofuranose, 4a-carba-beta-D-ribofuranose, 4a-carba-beta-L-arabinofuranose, and 4a-carba-beta-L-lyxofuranose) and four (carbafuranosyl)thiols [(4acarba-beta- D-xylofuranosyl)thiol, (4a-carba-beta-D-ribofuranosyl)thiol, (4a-carba-beta-L-arabinofuranosyl)- thiol, and (4a-carba-beta-L-lyxofuranosyl)thiol] were assembled. From this study, it was shown that these constructions tolerate a variety of precursors, and in many instances, they are suitable for scaling-up.