Academic literature on the topic 'NEU-Med'

SummaryOb in der Drogerie oder in der Apotheke: Die Fülle von Nahrungsergänzungsmitteln ist enorm. Hinzu kommen neu erscheinende Studien sowie zahlreiche Werbebotschaften. Dadurch ist es oft schwierig, den Überblick über relevante Mittel und ihre validen Anwendungsmöglichkeiten zu behalten. Im Gespräch mit Dr. med. Volker Schmiedel erfahren wir mehr über verschiedene Zusammenhänge und sinnvolle sowie womöglich weniger sinnvolle Anwendungen von Nahrungsergänzungsmitteln.

Abstract. In this study we analyze drought features at the European level over the period 1901–2019 using three drought indices: the standardized precipitation index (SPI), the standardized precipitation evapotranspiration index (SPEI), and the self-calibrated Palmer drought severity index (scPDSI). The results based on the SPEI and scPDSI point to the fact that Central Europe (CEU) and the Mediterranean region (MED) are becoming dryer due to an increase in the potential evapotranspiration and mean air temperature, while North Europe (NEU) is becoming wetter. By contrast, the SPI drought does not reveal these changes in the drought variability, mainly due to the fact that the precipitation does not exhibit a significant change, especially over CEU. The SPEI12 indicates a significant increase both in the drought frequency and area over the last three decades for MED and CEU, while SPI12 does not capture these features. Thus, the performance of the SPI may be insufficient for drought analysis studies over regions where there is a strong warming signal. By analyzing the frequency of compound events (e.g., high temperatures and droughts), we show that the potential evapotranspiration and the mean air temperature are becoming essential components for drought occurrence over CEU and MED. This, together with the projected increase in the potential evapotranspiration under a warming climate, has significant implications concerning the future occurrence of drought events, especially for the MED and CEU regions.

Background : Colorectal carcinoma (CRC) is the most frequently observed malignancy worldwide. The incidence of CRC is 3.5% in Bangladesh. Conflicting data exist about the prevalence of HER-2/neu over expression in colorectal cancer ranging from 0 to 83%. The aim of this study was to evaluate the expression of Her-2/neu protein in colorectal cancers. Materials and methods: This descriptive cross-sectional study was conducted in the Department of Pathology of Chittagong Medical College, Chittagong, Bangladesh from 1st January 2017 to 31st December 2017. A total of 52 cases with a histopathological diagnosis of colorectal cancers included in the study as sample size, HER2 status was evaluated by immunohistochemistry (IHC) in formalin fixed, paraffin embedded tissue.Positive expression was assigned a score from 0–3+.IHCs were analysed with grades of colon cancers. Results: The mean age in this study was 47.62years range from 12 to 85 years ,53.8% were female. Among 52 specimens 30 (57.7%) cases were from colon and all the cases were adenocarcinoma and rest of all (42.3%) were from rectum.33 (63.5%) cases were Grade-I, 8 (15.4%) were Grade-II, and 11 (21.2%) were Grade-III. Only 8 (15.4%) of 52 cases showed HER2 positive, 4 (50.0%) cases were from grade- Iand another 4 (50.0%) were grade- II tumours. HER2 overexpression were significantly associated with well differentiated CRC than poorly differentiated (p=0.044). Conclusion: HER2/neu protein expression was observed in colorectal cancer but HER-2/neu protein is less likely to be expressed in colon cancer cell lines among our patients. Chatt Maa Shi Hosp Med Coll J; Vol.21 (1); January 2022; Page 52-56

582 Background: DD q 2 weekly (w) AC → T is superior to conventionally scheduled (cs) AC → T and safe w/long follow-up (Hudis et al, SABCS 2005). With q 3 wk AC, adjuvant (adj) H is safe and effective (Romond et al and Perez et al, NEJM 2005). We therefore tested DD q 2 w AC → T + H × 1 year (y) as adj treatment (Rx) of patients (pts) with HER2/neu (+) BCA to determine cardiac safety. Based on the reported cardiac event (CE) rate of ≤ 4% in the randomized trials using cs chemotherapy (CRx) + H, we evaluated DD q 2 w AC → T + H with a 1° endpoint of cardiac safety defined as discontinuation (DC) of H due to 1) cardiac death or 2) congestive heart failure (CHF). The 2° endpoint is time to recurrence and overall survival. Methods: Pts with HER2/Neu IHC 3+ or FISH-amplified BCA were enrolled, regardless of tumor size or nodal status. Rx consisted of AC at 60/600 mg/m2 × 4 → T at 175 mg/m2 × 4 q 2 w w/pegfilgrastim 6 mg on d 2 + H × 1 y. Multi-gated radionuclide angiography scan (MUGA) is obtained at baseline and at months (mo) 2 (after AC × 4), 6 (after T × 4), 9, and 18. Pts w/baseline LVEF of ≥ 55% and w/o cardiac illnesses are eligible. Pts w/significant (sig) asymptomatic (asx) LVEF ↓ after DD AC based on mo 2 MUGA did not receive H, and pts w/sig asx LVEF ↓ during H had it DC’d. If the CE rate is > 4%, Rx is deemed not feasible. Results: From January 4, 2005 to November 1, 2005, 70 pts were enrolled. Median (med) age is 49 years (range, 27–72). Forty one of 70 pts (60%) had node (+) BC and 27/70 pts (40%) had (-) nodes. Med baseline LVEF is 68% (range, 55%-81%). As of January 9, 2005, all pts had mo 2 MUGA after DD AC and there is no sig LVEF ↓ and the med LVEF is 67% (range, 58%-79%). To date 39 pts had mo 6 MUGA w/med LVEF of 66% (range, 56%-75%) and one pt had a sig asx LVEF ↓ from baseline of 74% to 56%; H was DC’d. Twenty-three pts had mo 9 MUGA w/a med LVEF of 64% (range, 57%-69%). One patient had clinical CHF at mo 4 w/EF of 45% and improved sig w/cardiac medications. One had pneumonitis during radiation (RT). One had atrial fibrillation w/pericarditis after completion of RT. Discussion: DD AC → T + H appears to have an acceptable cardiac toxicity profile w/1/70 pts having a CE. Updated cardiac safety data will be presented. [Table: see text]

Introduction: Now a days immunohistochemistry and genomic testing for patient with Non- Small Cell Lung Cancer (NSCLC) is becoming new standard of care in clinical decision making. A renewed interest has been emerging on the human epidermal growth factor-2 (HER2) pathway. Aim of this present study was clinicopathological correlation of HER-2/neu expression by IHC in NSCLC. Method: This was a Cross sectional and observational study done at Sir Salimullah Medical College and National Institute of Disease of the Chest and Hospital (NIDCH) and other private hospitals in Dhaka city during July / 2014 to June / 2016. Adult of both gender with histologically diagnosed as a case of NSCLC was include in the study. Immunohistochemistry was done to see the positivity for HER/neu and clinical characteristics were observed. Result: A total 45 patients with NSCLC were enrolled in the study. Male was 77.8% (n=35) and female was 22.2% (n=10). The mean age was 55.67 (SD± 12) years and mean age of male was higher compared to female (57.54±11.64 years verses 49.1±11.38 years). Most of the male were smokers (71.1%) and female were nonsmokers (90%). 57.78% (n=26) of patients and 42.22% (n=19) of patients had adenocarcinoma and squamous cell carcinoma respectively. Most squamous cell carcinoma patients were elderly, had wasting and having higher TNM staging. Serum LDH level was higher with advance staging and grading. Only 8.89% (n=4) had HER-2/neu positive expression affected by male. Patients with HER 2/neu positive expression were relatively older (mean age 62.5±17.08). However, there were equal in histopathological categorization (50% SCC and 50% Adenocarcinoma). Mean LDH was slightly higher in HER-2 positive patients was compared to HER-2 negative patients (569.5±232.6 versus 469.7±181.8). Conclusion: About nine percent of patients having HER-2/neu positive was relatively older and had more high level of LDH. A large-scale study should be conducted in Bangladeshi population to characterize epidemiological, clinicopathological feature in patients with NSCLC with HER-2 expression. J Dhaka Med Coll. 2021; 29(1): 99-110

Genetic parameters for liveweight (LWT), greasy fleece weight (GFW), mean fibre diameter (MFD), standard deviation of MFD (MFD-s.d.), mean fibre curvature (CURVE) percentage of medullated (%MED) and kemp (%KEMP) fibres, faecal worm egg count (WEC), packed cell volume (PCV), mean corpuscular volume (MCV) mean corpuscular haemoglobin content (MCHC), circulating anti-nematode IgG (IgG) and counts of circulating eosinophils (EOS), lymphocytes (LYM), neutrophils (NEU), basophils (BASO) and monocytes (MONO) up to 18 months of age were estimated in Australian Angora goats (608 animals, 14 sires 3 years of birth). Measurements were made during a period of natural parasite challenge up to 5 months of age, or following artificial challenge with 10 000 infective larvae of Trichostrongylus colubriformis at 5.25 months of age. Year of birth had a significant impact on production and parasite-associated traits at all ages studied. Sex had a marked effect on production and erythrocyte traits. Birth type had no effect on any traits in animals older than 6 months. Maternal effects were not significant except for LWT at 3, 5 and 6 months and for IgG at 3 months. Most production traits were highly (LWT, GFW, MFD, %MED) or moderately (CURVE, MFD-s.d.) heritable (range 0.17–0.59) with only %KEMP having a low heritability (0.02–0.14). The heritability estimates (±s.e.) for CURVE are novel for goats and ranged from 0.18 ± 0.09 at first shearing to 0.44 ± 0.14 at third shearing. Heritability estimates were low for WEC (0.02–0.16) and for specific IgG during natural infection (0.14–0.15) but higher for IgG following artificial challenge with T. colubriformis (0.42 ± 0.13). Of the haematological variables NEU and all red cell traits were highly heritable (0.45–0.71), LYM and MONO were moderately to highly heritable (0.31–0.55), and EOS was weakly to moderately heritable (0.06–0.28). Strong phenotypic correlations existed between production traits. MFD was positively correlated with GFW and negatively correlated with CURVE, indicating that finer fibres have a higher crimp or wave count. WEC had consistent negative phenotypic correlations with PCV, LYM and EOS, and positive correlations with NEU. Correlations with IgG were positive up to 5 months and negative thereafter. Phenotypic correlations between WEC and LWT as well as with GFW and MFD were negative. Heritability estimates for production traits were generally consistent with other studies. Haematological and fibre curvature findings are completely novel for Angora goats. Estimates of heritability for WEC fell in mid range of published findings for other goat breeds, and these results suggest that there is some scope for breeding for worm resistance in Angoras but the response is likely to be slow.

Background & objective: The importance of establishing hormone receptor status of tumors for the treatment of women with hormone receptor-positive breast cancer is often emphasized. It is critical to evaluate hormone receptor status when considering response to endocrine therapy. The present study was intended to evaluate the usefulness of hormone receptor status in breast carcinoma. Materials & Methods: The present study was conducted in the Department of Pathology, Dhaka Medical College, Dhaka over a period 12 months from July 2009 to June 2010. A total of 30 histopathologically diagnosed cases of breast tumors who were also subjected to immunohistochemical (IHC) test for ER, PR status and HER-2/neu were consecutively included in the study. Patients who have already been treated for malignancy or who had a history of receiving radiotherapy were excluded. Result: Age distributions shows that 40% of the patients were early middle-aged (30-40 years), 30% middle-aged and the rest were either < 30 years or >50 years old. Left breast was involved more often (56.7%) than the right breast (43.3%). The predominant location was upper outer quadrant (43.3%), followed by upper inner quadrant (20%), lower outer quadrant (20%), lower inner quadrant (10%) and central (6.7%). Over half (53.3%) of the tumors were < 5 cm and the rest 5 cm or more. Nearly half (46.7%) of the tumors were moderately differentiated, 36.6% well-differentiated and 16.7% poorly differentiated. In majority (83.3%) of the cases lymph-nodes (axillary lymph nodes) were involved. Based on estrogen and progesterone receptor status, over half (53.3%) of the tumors were ER and PR positive and 40% were Her2/neu overexpressed. Conclusion: The study concluded that half of the Bangladeshi breast cancer patients are ER and PR positive and two in every five cases are Her2/neu overexpressed. J Shaheed Suhrawardy Med Coll, December 2018, Vol.10(2); 70-73

La presente Tesi di Dottorato riguarda lo studio geoarcheologico condotto all’interno di un contesto territoriale della Toscana centro-meridionale compreso tra i rilievi delle Colline Metallifere, i bacini idrografici dei fiumi Pecora e Cornia, e l’area costiera tirrenica tra Piombino e Follonica (Toscana centro-meridionale). La ricerca si è svolta nell’ambito di un progetto ERC multidisciplinare riguardante la caratterizzazione storica, archeologica e ambientale del territorio sotto esame durante i secoli altomedievali (VII-XIII sec AD). Per gli scopi del progetto, la ricerca ha proposto l’integrazione di metodi geoarcheologici (analisi geomorfologica, Remote Sensing, sedimentologia, stratigrafia sia di superficie che di sottosuolo e analisi micromorfologica) in un approccio basato sull’analisi Multiscala (Macroscala, Mesoscala e Microscala). L’impostazione della ricerca su questi tre livelli di risoluzione ha permesso di selezionare un ampio spettro di dati utili per ricostruire, in alto dettaglio, sia la cronologia degli eventi occorsi nella modellazione del paesaggio fisico storico sia le complesse interazioni con le attività antropiche. Inoltre, questo approccio ha consentito di analizzare le dinamiche insediative ed i processi di formazione, occupazione ed abbandono del sito altomedievale di Vetricella, ubicato nella pianura costiera del fiume Pecora, e considerato un unicum nell’area di studio sia per la sua posizione sia per le sue caratteristiche insediative. In particolare, i risultati della Macroscala suggeriscono come, alla scala del singolo bacino idrografico e delle aree costiere, l’evoluzione delle dinamiche di modellazione del paesaggio fisico e biologico durante l’Altomedioevo non fosse influenzata dalle supposte variazioni climatiche, che pure sono contraddittoriamente note in letteratura per il periodo storico in analisi, ma sia piuttosto il risultato di profonde modificazioni delle dinamiche superficiali ad opera dell’azione antropica, determinandone l’assetto odierno. La definizione degli effetti sul paesaggio delle attività umane fornisce quindi nuove informazioni circa le capacità gestionali e pianificatorie e tecnologiche del land use e quindi della loro importanza in ottica storica e socio-economica. Le analisi alla Mesoscala, invece, evidenziano come il sito archeologico di Vetricella fosse localizzato all’interno di un contesto dove la scelta dell’insediamento, e di conseguenza le sue funzioni, era stata pianificata allo scopo di mitigare la pericolosità associata allo scorrimento delle acque superficiali e dei rischi associati. Infine, le analisi alla Microscala delineano un quadro in cui l’adattamento al contesto geomorfologico è stato frutto di una accurata e continua pianificazione di opere di costruzione/distruzione di piani d’uso e di sistemazioni idrauliche. In particolare, quest’ultime sono relative alla presenza di tre fossati concentrici i cui riempimenti restituiscono un record sedimentologico e stratigrafico che suggerisce il loro utilizzo per scopi diversi legati ad attività produttive, difensive e domestiche. Nel complesso, l’approccio Multiscala si è rivelato decisivo per definire un quadro di riferimento cronologico dell’evoluzione del paesaggio all’interno dei sistemi vallivi nonché delle profonde modificazioni apportate dalle attività antropiche e delle loro relazioni con l’evoluzione a lungo, medio e breve termine degli ambienti umidi costieri. Per la prima volta, quindi, è stato possibile determinare come questi contesti, ritenuti per l’Altomedioevo difficilmente colonizzabili od esclusi dalla rete insediativa, fossero in realtà gestiti attraverso una precisa volontà di pianificazione delle opere di sistemazione idraulica e di sfruttamento delle risorse agricole e forestali.

The use of proteins or peptides as immunogens is attractive for the development of vaccines, especially cancer vaccines, but requires efficient and safe adjuvant formulations to overcome their intrinsic weak immunogenicity. Although dozens of different adjuvants have been shown to be effective in preclinical and clinical studies, alum remains the only one approved for human use in the USA and the most employed worldwide, but it turned out to be inefficient in cancer vaccine formulations. Indeed, the prerequisites for an ideal cancer adjuvant differ from conventional adjuvants. Since cancer vaccines target self-antigens, the ideal cancer adjuvant must be extremely potent to circumvent immune tolerance, but it must also be safe to avoid autoimmune reactions. Of note, recent studies indicate that effective therapeutic and preventive cancer vaccines require the induction of a more balanced T helper 1 (Th1)/Th2 immune response, characterized by the presence of a strong cytotoxic CD8+ T lymphocyte (CTL) activity, and the production of IgG subclasses with specific effector functions. For example, efficient tumor prevention in mice is associated with high levels of IgG2a and IgG2b subclasses, which are considered the most potent inducers of complement-dependent cytotoxicity (CDC) and antibody-dependent cell-mediated cytotoxicity (ADCC) in rodents. To solve all these problems, new generation vaccines often incorporate toll-like receptors (TLRs) agonists. Among them, natural polymers (NPs) that can act as damage-associated molecular patterns (DAMPs) or pathogen-associated molecular patterns (PAMPs), are emerging as a new efficient class of vaccine adjuvants due to their ability to orchestrate the cross-talk between innate and adaptive immunity. In particular, NPs induce the maturation of dendritic cells (DCs) and finely regulate the balance between Th1 and Th2 responses, thus inducing potent and long-lasting humoral and cellular responses. Moreover, they are biocompatible, biodegradable, non-toxic, non-immunogenic, and non-inflammatory. This project aimed at validating our NP, called NPX for patent constraints, as a new TLR agonist and carrier of immunogens for the design of more efficient and safer cancer vaccines, and comparing its adjuvanticity with alum. To this aim, NPX was chemically linked to the extracellular domain (ECD) of the rat form of the epidermal growth factor receptor (rHER2/neu), or to short peptide sequences derived from the ECD of rHER2/neu, and the resulting bioconjugates were used for immunization of both BALB/c and BALB-neuT transgenic mice. In this work, we demonstrated that NPX has an extremely satisfactory safety profile, as no local side effects were observed in vaccinated mice. Moreover, NPX induced strong antigen-specific immune reactions very efficiently. In fact, even though both alum- and NPX-adjuvanted formulations induced high humoral immune responses against rHER2/neu, NPX-vaccinated BALB/c mice disclosed IgG titers that were about two-fold higher than those calculated for alum. Of note, only conjugation with NPX induced a detectable humoral response against rHER2/neu-derived peptides. Both adjuvants induced high production of different IgG subclasses, but despite similar IgG1 titers NPX-vaccinated mice disclosed also higher IgG2a and IgG2b levels. The strong elicitation of the three IgG subclasses and the production of both Th1 and Th2-type cytokines such as IL-12p70, IFN-γ, IL-2, IL-6, and IL-10, confirmed the ability of NPX to induce a balanced Th1/Th2 response. Moreover, the different quality and quantity of IgG subclasses, and their superior ability to recognize rHER2/neu in its native conformation likely reflected on the better functionality of NPX-induced antibodies in triggering complement-mediated specific lysis of rHER2/neu-positive cells. Interestingly, NPX not only induced humoral responses that persisted over time, but also selected mature B cell clones secreting antibodies with an improved ability to bind rHER2/neu in its native conformation and to mediate effector functions. The robust immune responses induced by NPX proved to be effective in both the prophylactic and therapeutic settings; indeed, NPX-adjuvanted vaccine formulation prevented and significantly delayed tumor growth in tumor challenged mice. Interestingly, antitumor responses seemed in part to be mediated by NPX ability to induce also CTL responses, which were detected only in NPX-vaccinated groups. Finally, while both alum- and NPX-adjuvanted vaccines proved to be successful in breaking tolerance against rHER2/neu in BALB-neuT transgenic mice, NPX-vaccinated mice displayed IgG titers that were two-fold higher than those observed with alum. Interestingly, in transgenic mice NPX vaccination resulted in a better Th1/Th2 balance than in BALB/c mice. However, only NPX-induced antibodies were able to recognize rHER2/neu in its native conformation. This likely explains the capacity of NPX-based vaccination to protect from or delay the growth of spontaneous tumors in BALB-neuT mice, whereas alum completely failed to induce any protective response. Taken together, our data show that NPX is a safe and powerful adjuvant that could be exploited for the development of new HER2/neu vaccination strategies. In fact, NPX is effective in enhancing the magnitude, breadth, quality, and longevity of specific humoral and cellular immune responses to antigens, without causing toxicity. Importantly, these effects can be achieved even with a strongly reduced antigen dose.
L’utilizzo di proteine o peptidi come immunogeni ha sempre rappresentato un’attrattiva per la creazione di vaccini, in particolare per i vaccini a scopo antitumorale; ciononostante, questo genere di formulazione richiede l’impiego di adiuvanti immunologici efficienti e sicuri che siano in grado di potenziare la scarsa immunogenicità degli antigeni stessi. Sebbene dozzine di adiuvanti si siano dimostrate efficienti in ambito preclinico e clinico, l’allume rimane il principale adiuvante ad uso umano impiegato in tutto il mondo, nonostante abbia dimostrato scarsa efficienza nell’ambito della vaccinazione antitumorale. I prerequisiti di un adiuvante antitumorale sono di fatto diversi da quelli dei classici adiuvanti. I vaccini antitumorali hanno infatti come target antigeni self, e dunque l’adiuvante antitumorale deve essere abbastanza potente da superarne la tolleranza immunologica, ma deve anche essere sicuro in modo da evitare fenomeni avversi di tipo autoimmune. Studi recenti hanno dimostrato che affinché i vaccini tumorali preventivi e terapeutici siano efficaci, si devono indurre risposte sia di tipo T helper 1 (Th1) che Th2, in grado di indurre sia una forte attività litica da parte dei linfociti CD8+ T citotossici (CTL) che la produzione di sottoclassi anticorpali capaci di mediare particolari funzioni effettrici. Ad esempio, nel topo è stata dimostrata una correlazione tra prevenzione tumorale e presenza di alti livelli di immunoglobuline IgG2a e IgG2b, considerate le più efficienti nell’induzione di citotossicità complemento-dipendente (CDC) e di citotossicità cellulo-mediata anticorpo-dipendente (ADCC). Per adempiere a tutte queste richieste, le nuove generazioni di vaccini spesso incorporano nella propria formulazione degli agonisti dei toll-like receptors (TLRs). Tra questi agonisti, i polimeri naturali (NP), che agiscono come damage-associated molecular patterns (DAMPs) o pathogen-associated molecular patterns (PAMPs), stanno emergendo come una nuova classe di efficienti adiuvanti immunologici grazie alla loro capacità di mediare l’interazione tra il sistema immunitario innato e adattativo. In particolare, essi sono in grado di indurre la maturazione delle cellule dendritiche (DCs) e di regolare accuratamente il bilancio tra le risposte di tipo Th1 e Th2, al fine di indurre potenti e durature risposte umorali e cellulari. Gli NP sono inoltre biocompatibili, biodegradabili, non tossici, non immunogenici e non infiammatori. Questo progetto di ricerca si è focalizzato sulla validazione del polimero naturale da noi sviluppato, cui ci riferiamo col termine NPX a causa di vincoli brevettuali, come nuovo agonista di TLR e veicolo di immunogeni per la creazione di vaccini antitumorali più efficienti e sicuri, comparando il suo profilo di adiuvanticità con quello dell’allume. A questo scopo, abbiamo coniugato NPX con il dominio extracellulare (ECD) del recettore 2 per il fattore di crescita epidermico di ratto (rHER2/neu) o con peptidi a breve sequenza amminoacidica derivati dall’ECD stesso. I bioconiugati così sintetizzati sono stati utilizzati per la vaccinazione di topi BALB/c e di topi transgenici BALB-neuT. In questo lavoro abbiamo innanzitutto dimostrato che NPX possiede un profilo d’azione estremamente sicuro, in quanto i topi immunizzati con tale adiuvante non hanno manifestato segni di tossicità a livello locale. NPX si è inoltre rivelato estremamente efficiente nell’indurre forti risposte immunitarie antigene-specifiche. Infatti, sebbene entrambi gli adiuvanti abbiano stimolato con successo elevate risposte umorali contro rHER2/neu, i topi BALB/c immunizzati con NPX hanno prodotto titoli di IgG doppi rispetto a quelli riscontrati nel gruppo trattato con l’allume. Inoltre solo NPX è riuscito a indurre la produzione di anticorpi in risposta alla vaccinazione con peptidi derivanti dalla porzione extracellulare del recettore. Entrambi gli adiuvanti hanno prodotto alti livelli delle differenti sottoclassi di anticorpi IgG; tuttavia, nonostante la produzione di IgG1 sia paragonabile, i livelli di IgG2a e IgG2b sono risultati nettamente maggiori negli animali vaccinati con NPX. Le elevate concentrazioni delle tre sottoclassi anticorpali e la produzione di citochine sia di tipo Th1, quali IL-12p70, IFN-γ e IL-2, che di tipo Th2, come IL-6 e IL-10, hanno confermato la capacità di NPX di indurre una risposta Th1/Th2 bilanciata. La differente qualità e quantità degli anticorpi prodotti e la loro migliore capacità di riconoscere il recettore nella sua conformazione nativa, probabilmente si riflettono nella migliore funzionalità degli anticorpi indotti da NPX nell’attivare la lisi cellulare rHER2/neu-specifica mediata dal complemento. In particolare, NPX si è dimostrato efficace non solo nell’indurre risposte umorali durature, ma anche nel selezionare cloni maturi di linfociti B secernenti anticorpi dotati di una migliore capacità di riconoscere il recettore nella sua forma nativa e di mediare le proprie funzioni effettrici. Le elevate risposte immunitarie indotte da NPX si sono dimostrate efficienti nell’ambito sia della vaccinazione preventiva che terapeutica, prevenendo o ritardando in entrambi i contesti la crescita tumorale nei topi inoculati con il tumore. Tali risposte sembrano inoltre essere almeno in parte dovute all’azione dei CTL, la cui presenza è stata riscontrata solamente negli animali immunizzati con NPX. Sia la vaccinazione con NPX che quella con l’allume si sono dimostrate in grado di rompere la tolleranza contro il recettore espresso costitutivamente nei topi transgenici BALB-neuT. Il gruppo vaccinato con NPX ha prodotto titoli anticorpali doppi rispetto al gruppo allume e un profilo di risposta Th1/Th2 ancora più bilanciato rispetto a quanto osservato nei topi BALB/c. Comunque, solo gli anticorpi indotti da NPX si sono dimostrati capaci di riconoscere il recettore nella sua conformazione nativa, e ciò spiegherebbe come questo tipo di vaccinazione riesca a conferire protezione o indurre ritardo nella crescita tumorale spontanea nei topi BALB-neuT. Al contrario, la vaccinazione con l’allume ha completamente fallito nell’indurre una qualsiasi risposta tumorale protettiva. Nell’insieme, i risultati ottenuti indicano che NPX è un adiuvante sicuro ed efficace, potenzialmente utilizzabile per la creazione di vaccinazioni antitumorali HER2-specifiche. Abbiamo infatti dimostrato che NPX migliora l’entità, l’ampiezza, la qualità e la longevità delle risposte immunitarie umorali e cellulo-mediate rispetto all’allume, senza causare effetti tossici e permettendo inoltre di utilizzare dosi ridotte di antigene.

Il nostro studio prospettico ha lo scopo di identificare dei parametri biomolecolari (EGFR, PTEN, p-Akt, HER3, c-Met, IGF1R) la cui espressione, nei carcinomi mammari metastatici HER-2/neu positivi, possa predire la risposta al trastuzumab, considerando che la percentuale di non progressione ad un anno dall’inizio del trattamento è del 40% circa. Materiali e Metodi: Sono state valutate l’espressione immunoistochimica di EGFR, PTEN, pAkt, HER, c-Met e IGF1R e l’amplificazione del gene EGFR tramite FISH in 101 carcinomi mammari metastatici HER-2/neu positivi trattati con trastuzumab. Le pazienti, con follow-up noto, sono state controllate fino al decesso o a settembre 2009. Le pazienti sono state distribuite (“modalità di risposta”) nei gruppi di resistenza, di refrattarietà o di risposta al trastuzumab. Sono stati considerati 13,0 mesi come cut-off per considerare una paziente come rispondente o non rispondente al trattamento. Risultati: Nella casistica, la percentuale di risposta al trastuzumab è del 40,2%. Lo stato recettoriale ha mostrato una correlazione statisticamente significativa diretta con PTEN (P=0,021 e P=0,005 per recettori estrogenici e progestinici) ed inversa con EGFR (P=0,006 per recettori estrogenici) e pAkt (P=0,031 per recettori progestinici). E’ stata evidenziata una correlazione bassa e inversa tra PTEN e pAkt (P<0,001). Esistono correlazioni statisticamente significative tra il parametro “modalità di risposta” e pAkt ed EGFR. L’analisi discriminante ha selezionato i parametri EGFR e pAkt con sensibilità del 57,6%, specificità del 73,8%, accuratezza del 64,4%, valore predittivo positivo del 75,5% e predittivo negativo del 55,4%. Conclusioni: La paziente, in virtù del suo profilo d’espressione, se assegnata al gruppo di predizione dei rispondenti, avrà una probabilità del 75,5% di rispondere al trastuzumab. Ciò va oltre quel 40% di risposta globale che non considera lo specifico profilo molecolare della neoplasia.
Aim: According to the literature, the patients with HER-2/neu positive metastatic breast cancer (MBC) who respond to treatment based on trastuzumab plus chemotherapy are less than 40%. The aim of this study was to identify features that help us to better predict the response to trastuzumabcontaining regimen in this group of patients. Materials and Methods: The immunohistochemical expression of EGFR, PTEN, pAkt, HER-3, c- Met and IGF1R and the EGFR gene status were evaluated in 101 cases of HER-2/neu+ MBC. All the patients had been treated with trastuzumab-based regimens and had a well-known follow-up until September 2009. According to the “type of response to treatment”, the patients were subdivided in three groups: resistant, refractory or respondent. The patients without progression in the first 13.0 months of trastuzumab-containing therapy were considered as responders, the other ones as non-responders. Results: The percentage of responders was 40.2%. A statistically significant direct relation was seen between PTEN expression and ER and PR expression (P=0.021 and P=0.005, respectively), whereas a negative one was present between ER and EGFR (P=0.006) and between PR and p-Akt expressions (P=0.031). A statistically significant low, inverse relation was seen between PTEN and pAkt (P<0.001). A statistically significant direct relation was seen between the “type of response to treatment” and pAkt and EGFR. A discriminant analysis was performed by using EGFR and pAkt. The sensibility was 57.6%, the specificity was 73.8%, the accuracy was 64.4%; positive predictive value was 75.5% and negative predictive value was 55.4%. Conclusions: We demonstrated that a mathematical model based on the immunohistochemical expression of EGFR and pAkt can increase the level of response prediction in patients with HER- 2/neu+ MBC treated with trastuzumab-containing regimen: 75.5% of patients mathematically assigned to “responders group” has a time to progression longer than 13 months.

Utilizzando il modello tumorale transgenico BALB-NeuT abbiamo analizzato la specifica interferenza, indotta dalla vaccinazione, della carcinogenesi causata in questo modello animale dal prodotto dell’oncogene neu. È stata confrontata l’inibizione della formazione di masse tumorali in seguito alla vaccinazione con neu di ratto normale (ErbB2/Neu) o con i recettori ErbB xenogenici umani (LTR-EGFR, LTR-ErbB2, LTR-ErbB3, LTR-ErbB4), espressi singolarmente in cellule murine NIH3T3, o in seguito alla vaccinazione con poxvirus ricombinante, Vaccinia virus (rV-neu). La vaccinazione precoce, allo stadio di iperplasia atipica con LTR-Neu, inibisce in maniera drastica la carcinogenesi mammaria mediata da neu e inoltre, la vaccinazione con cellule esprimenti i recettori ErbB umani interferisce, significativamente in tutti i casi, con lo sviluppo del tumore nei topi BALB-NeuT. L’aumento relativo nella sopravvivenza libera da tumore e la riduzione dell’incidenza dei tumori corrisponde alla conservazione strutturale condivisa tra i recettori umani e l’oncogene neu, infatti l’immunizzazione con cellule trasfettate con LTR-Neu è quella che ha mostrato la maggiore efficacia antitumorale seguita da LTR-ErbB2 e dagli altri tre recettori ErbB umani. Le vaccinazioni hanno dimostrato di indurre un alto, specifico e comparabile titolo anticorpale e gli effetti antitumorali indotti da questi anticorpi correlano con la cross reattività verso il dominio extracellulare, purificato in vitro, della proteina Neu. Inoltre una specifica risposta T cellulare verso epitopi del Neu di ratto, rilevabile per la reattività di queste cellule alla stimolazione con peptidi specifici, è stata anche stimolata nelle cellule di milza dei topi immunizzati con LTR-Neu e, in misura minore, nelle cellule dei topi immunizzati con LTR-ErbB2 e LTR-EGFR. L’inibizione tumorale più pronunciata in seguito alla vaccinazione con LTR-Neu è stata associata con l’infiltrato leucocitario e la necrosi tumorale in vivo, mentre i sieri immuni specificamente inducono citotossicità cellulo mediata dipendente dagli anticorpi e apoptosi delle cellule tumorali mammarie dei topi BALB-NeuT in vitro. Inoltre, valutando l’efficacia di un vaccino che usa come veicolo il virus vaccinico ricombinante per Neu, si è rilevata la capacità anche di questa immunizzazione di contrastare efficacemente la crescita dei tumori nei topi transgenici con un effetto più marcato per inoculi multipli. L’inibizione risultante è comparabile alla vaccinazione allogenica quando le somministrazioni sono effettuate agli stadi più precoci di sviluppo del tumore mentre induce una protezione superiore ad essa quando l’immunizzazione con il virus ricombinante è eseguita a partire da uno stadio tardivo di sviluppo della malattia.
Employing the transgenic animal model BALB-NeuT, the outcome of neu-mediated tumorigenesis was compared following vaccination with isogenic normal rat ErbB2/Neu (LTR-Neu) or xenogeneic human ErbB receptors (LTR-EGFR, LTR-ErbB2, LTR-ErbB3 and LTR-ErbB4), both recombinantly expressed in an NIH3T3 murine cell background, or following vaccination with neu-recombinant Vaccinia virus (rV-neu). Vaccination using rat LTR-Neu at the stage of atypical hyperplasia potently inhibited neu-mediated mammary tumorigenesis. Moreover, all human ErbB receptors specifically interfered with tumor development in BALB-NeuT mice. Relative increase in tumor-free survival and reduction in tumor incidence corresponded to structural similarity shared with the etiologic neu oncogene. The rat orthologue LTR-Neu proved most effective followed by the human homologue LTR-ErbB2 and then the other three human ErbB receptors. Vaccination resulted in high titer of specific serum antibodies whose tumor-inhibitory effects correlated with cross-reactivity to purified rat Neu extracellular domain in vitro. Furthermore, a T cell response specific for peptide epitopes of rat Neu was elicited in spleen cells of mice immunized with LTR-Neu and was remotely detectable for discrete peptides upon vaccination with LTR-ErbB2 and LTR-EGFR. The most pronounced tumor inhibition by LTR-Neu vaccination was associated with leukocyte infiltrate and tumor necrosis in vivo, while immune sera specifically induced cytotoxicity and apoptosis of BALB-NeuT tumor cells in vitro. Moreover, the multiple vaccination employing the neu-recombinant virus also resulted in a specific inhibition of neu-mediated tumorigenesis. The resulting inhibition was comparable with the allogeneic immunization schedule when started early in tumor development but gave higher protection when the vaccination was started later in tumor onset.

Ichthyoses – Bullous Congenital Ichthyosiform Erythroderma – Continual Peeling Skin – Harlequin Fetus – Ichthyosis Bullosa of Siemens – Ichthyosis Hystrix – Ichthyosis Vulgaris – Lamellar Exfoliation of the Newborn – Lamellar Ichthyosis/Nonbullous Congenital Ichthyosiform Erythroderma – Netherton Syndrome – Restrictive Dermopathy – X-linked Recessive Ichthyosis – Erythrokeratodermas – Erythrokeratodermia Variabilis – Pityriasis Rubra Pilaris – Progressive Symmetric Erythrokeratoderma – Acrokeratoderma – Acrokeratoelastoidosis – Acrokeratosis Verruciformis (HOPF) – Hereditary Palmoplantar Keratodermas – Hereditary Palmoplantar Keratoderma with Deafness – Hereditary Palmoplantar Keratoderma Epidermolytic Hyperkeratosis – Hereditary Palmoplantar Keratoderma Howel-Evans – Hereditary Palmoplantar Keratoderma Olmsted – Hereditary Palmoplantar Keratoderma Punctate – Hereditary Palmoplantar Keratoderma Striata – Hereditary Palmoplantar Keratoderma Unna-Thost – Hereditary Palmoplantar Keratoderma Vohwinkel – Keratolytic Winter Erythema – Mal de Meleda – Papillon-Lefèvre – Scleroatrophic and Keratotic Dermatosis of the Limbs – Porokeratoses – Porokeratosis of Mibelli – Other Disorders of the Epidermis – Absence of Dermatoglyphics – Acanthosis Nigricans – Darier-White Disease – Hereditary Painful Callosities – Keratosis Follicularis Spinulosa Decalvans – Knuckle Pads – Kyrle/Flegel Disease – Ulerythema Ophryogenes – Syndromic Disorders – CHILD Syndrome – Chondrodysplasia Punctata – Ichthyosis with Hypogonadism – KID Syndrome – Neu-Laxova Syndrome – Neutral Lipid Storage Disease with Ichthyosis – Refsum Disease – Richner-Hanhart Syndrome – Sjögren-Larsson Syndrome – Cohesion – Epidermolysis Bullosa – Epidermolysis Bullosa Simplex Dowling-Meara – Epidermolysis Bullosa Simplex Generalized – Epidermolysis Bullosa Simplex Localized – Epidermolysis Bullosa Junctional Generalized – Epidermolysis Bullosa Junctional Generalized Atrophic Benign – Epidermolysis Bullosa Dystrophica Cockayne-Touraine – Epidermolysis Bullosa Dystrophica, Hallopeau-Siemens – Epidermolysis Bullosa Dystrophica Pretibial – Transient Bullous Dermolysis of the Newborn – Hailey-Hailey Disease

Chapter 2 covers Ichthyoses (Bullous Congenital Ichthyosiform Erythroderma, Harlequin Ichthyosis, Ichthyosis Bullosa of Siemens, Ichthyosis Hystrix, Ichthyosis Vulgaris, Lamellar Exfoliation of the Newborn, Lamellar Ichthyosis/Nonbullous Congenital Ichthyosiform Erythroderma, Netherton Syndrome, Peeling Skin Syndrome, Restrictive Dermopathy, and X-linked Recessive Ichthyosis), Erythrokeratodermas (Erythrokeratodermia Variabilis ET PROGESSIVA, and Pityriasis Rubra Pilaris), Acrokeratoderma (Acrokeratoelastoidosis, Acrokeratosis Verruciformis (HOPF)), Hereditary Palmoplantar Keratodermas (Hereditary Palmoplantar Keratoderma with Deafness, Hereditary Palmoplantar Keratoderma Epidermolytic Hyperkeratosis, Hereditary Palmoplantar Keratoderma Howel-Evans, Hereditary Palmoplantar Keratoderma Olmsted, Hereditary Palmoplantar Keratoderma Punctate, Hereditary Palmoplantar Keratoderma Striata, Hereditary Palmoplantar Keratoderma Unna-Thost, Hereditary Palmoplantar Keratoderma Vohwinkel, Keratolytic Winter Erythema, Mal de Meleda, Papillon-Lefèvre, Scleroatrophic and Keratotic Dermatosis of the Limbs), Porokeratoses (Porokeratosis of Mibelli), Other Disorders of the Epidermis (Absence of Dermatoglyphics, Acanthosis Nigricans, Darier-White Disease, Hereditary Painful Callosities, Keratosis Follicularis Spinulosa Decalvans, Knuckle Pads, Kyrle/Flegel Disease, Ulerythema Ophryogenes), Syndromic Disorders (CHILD Syndrome, Chondrodysplasia Punctata, Ichthyosis with Hypogonadism, KID Syndrome, Neu-Laxova Syndrome, Neutral Lipid Storage Disease with Ichthyosis, Refsum Disease, Richner-Hanhart Syndrome, Sjögren-Larsson Syndrome), Cohesion (Epidermolysis Bullosa, Epidermolysis Bullosa Simplex Dowling-Meara, Epidermolysis Bullosa Simplex Generalized, Epidermolysis Bullosa Simplex Localized, Epidermolysis Bullosa Junctional Generalized, Epidermolysis Bullosa Junctional Generalized Atrophic Benign, Epidermolysis Bullosa Dystrophica Cockayne-Touraine, Epidermolysis Bullosa Dystrophica, Hallopeau-Siemens, Epidermolysis Bullosa Dystrophica Pretibial, Transient Bullous Dermolysis of the Newborn, Hailey-Hailey Disease). Each condition is discussed in detail, including dermatologic features, associated anomalies, histopathology, basic defect, treatment, mode of inheritance, prenatal diagnosis, and differential diagnosis.

This chapter reviews the various types of congenital ichthyoses that can present in the newborn with erythroderma, hyperkeratosis, scales, or fissures. The presenting symptoms frequently overlap in these conditions. Erythroderma is a finding frequently seen in the ichthyoses but as well in infection, atopy, immunodeficiency and some metabolic disorders. Common ichthyoses include Harlequin ichthyosis, lamellar ichthyosis, epidermolytic ichthyosis and X-linkedLinked ichthyosis. Important syndromes include Sjogren Larsson, trichothiodystrophy, CHILD syndrome and Gaucher Disease type II. Lethal ichthyosis syndromes include Neu Laxova and Restrictive Dermopathy. Harlequin ichthyosis is also frequently lethal. Gene panels increasingly should be the first line diagnostic test. The clinical case presentation features an infant with Netherton syndrome.

This chapter reviews the incidence, risk factors, genetics, recurrence risk, and epidemiology of isolated and syndromic non-immune hydrops fetalis (NIH). The discussion on the differential diagnosis of various types of NIH summarizes common causes, including chromosome anomalies (Down syndrome, Turner syndrome and others), congenital infections ( CMV, Parvovirus and Syphilis) , and multiple congenital anomaly syndromes (Noonan spectrum disorders, Neu Laxova syndrome, Hennekam syndrome and others), skeletal dysplasias and a number of lysosomal storage diseases. A through evaluation both before and after birth including maternal history, infectious work-up, microarray, autopsy and selected molecular testing including exome sequencing can achieve a diagnosis in an increasing number of cases. The mortality and morbidity of NIH remains high and relatively few are amenable to specific interventions. A clinical case presentation features an infant with congenital parvovirus B19 infection.