Search

This work presents a temporary settlement analysis of Casentino and Valtiberina, from the 7th to the 5th century BCE. During this period, these regions may have constituted an area of Apennine interconnectivity. Over time, they became the hinterland to one or more local political entities. To demonstrate these points, I begin by creating a theoretical model of the relationship between aristocratic and civic networks and the movement of professional artisans in the hinterland. The activity of these professionals in Casentino and Valtiberina becomes clear through singling out relevant patterns in material culture and building techniques. The final diachronic analysis of these patterns shows a drastic change in local settlement strategies in the middle of the 6th century BCE. This change can be related to simultaneous processes recorded along the rest of the Tiber Valley, perhaps resulting from the political influence of Clusium and its allies. To conclude, two different areas of settlement are interpreted as two hinterlands belonging to different cities, namely Arretium and Faesulae.

Cardiac tumors can be primary (benign or malignant) or metastatic (malignant) and can arise in any part of the heart tissue, causing obstruction in the inflow or outflow tract of the valves, thromboembolism, arrhythmias and pericardial disorders. Diagnosis is made by echocardiography and, frequently, by cardiac MRI. The treatment of metastatic malignancies depends on the type and origin of the tumor; however, the prognosis is generally poor.73–year–old patient, he reaches echocardiographic control after having started, 5 months earlier, chemotherapy with weekly carboplatin–paclitaxel scheme for the diagnosis of primary left hilar pulmonary heteroplasia. In medical history: systemic arterial hypertension, iron deficiency anemia and thrombocytopenia in a patient with a history of alcohol–related liver cirrhosis and esophageal varices.On transthoracic echocardiogram (Figures 1 and 2): normal size and bi–ventricular systolic function; mild aortic and mitral insufficiency. Presence of non–mobile isoechoic oval mass adhering to the left atrium, 43 x 27 mm in size, at the outlet of the left pulmonary veins, which does not cause obstruction to the atrio–ventricular blood supply.On CT of chest without and with contrast (Figure 3): primary heteroplastic left hilar pulmonary lesion that infiltrates the left atrium and obliterates the left main bronchus before the bifurcation and the bronchus for the left upper lobe; the corresponding pulmonary vessels also appear infiltrated. The diagnosis was therefore of intracardiac tumor secondary to primary lung lesion.Secondary cardiac tumors are about 20 times more frequent than primary ones. The ability of the tumor to spread to the heart depends on the relationship between the specific biological potential of the primary tumor, the location of the latter and the contractile and draining force of the myocardium.Cardiac metastases can involve, also in combination, pericardium, epicardium, myocardium, endocardium, heart chambers or create endocavitary neoplastic thrombus. Tumors spread to the heart through four possible routes: direct extension, the blood route, the lymphatic route, intracavitary diffusion from the inferior vena cava or pulmonary veins, as in our case.The haemodynamic alterations they cause depend on the engagement of the atrioventricular orifice by the tumor mass.

78–year–old man, hypertensive, diabetic, dyslipidemic, with a recent diagnosis of chronic ischemic encephalopathy and cognitive impairment that severely limited the acquisition of both proximate and remote pathological anamnesis.Transported to the emergency room from 118, contacted by family members, due to pain in the left arm associated with cold sweating and general malaise, symptoms lasting about 4 hours and no longer present upon arrival in the emergency room.On the Echocardiogram performed in ER: akinesia of the apex in its entirety and of the middle anterior wall, not present in a previous examination in April. To laboratory tests: first determination of the high sensitivity troponin within the limits of the norm. On ECG: sinus rhythm at 96 bpm, PR interval 144 ms, left axial deviation, elevation of the ST tract. at J point 2 mm) of the T wave, in the anterior precordials.This electrocardiographic aspect is typically present in the absence of pain, while the electrocardiographic trace generally normalizes in presence of pain.After coronary revascularization, most patients show normalization of the electrocardiogram and often of sectoral abnormalities of left ventricular function, suggesting that underlying the electrocardiographic and echocardiographic changes observed in Wellens is a mechanism of myocardial hibernation or stunning.

Background Amelanotic/hypomelanotic lentigo maligna and lentigo maligna melanoma (AHLM/LMM) may be very difficult to diagnose at an early stage. Objectives To quantify the predictive value of dermoscopic and reflectance confocal microscopy (RCM) features for AHLM/LMM. Methods Dermoscopic and RCM images of histopathologically diagnosed AHLM/LMM, amelanotic/hypomelanotic benign lesions (AHBL), and amelanotic/hypomelanotic basal and squamous cell carcinomas (AHBCC/AHSCC) of the head and neck from consecutive patients were retrospectively collected and blindly evaluated by three observers to assess presence or absence of dermoscopic and RCM criteria. Results Overall, 224 lesions in 216 patients including LM/LMM (n = 55, 24.6%), AHBL (n = 107, 47.8%) and AHBCC/AHSCC (n = 62, 27.7%) were analysed. Multivariable analysis showed that milky-red areas (OR = 5.46; 95% CI: 1.51-19.75), peripheral light brown structureless areas (OR = 19.10; 4.45-81.96), linear irregular vessels (OR = 5.44; 1.45-20.40), and asymmetric pigmented follicles (OR = 14.45; 2.77-75.44) at dermoscopy, and >= 3 atypical cells in five fields (OR = 10.12; 3.00-34.12) and focal follicular localization of atypical cells at dermo-epidermal junction (DEJ) (OR = 10.48; 1.10-99.81) at RCM were significantly independent diagnostic factors for AHLM/LMM vs. AHBL. In comparison with AHBCC/AHSCC, peripheral light brown structureless area (OR = 7.11; 1.53-32.96), pseudonetwork around hair follicles (OR = 16.69; 2.73-102.07), and annular granular structures (OR = 42.36; 3.51-511.16) at dermoscopy and large dendritic (OR = 6.86; 3.15-38.28) and round pagetoid cells (OR = 26.78; 3.15-227.98) at RCM led to a significantly increased risk of diagnosing AHLM/LMM. Conclusions Amelanotic/hypomelanotic lentigo maligna and lentigo maligna melanoma may have the same dermoscopic features of AHM on other body sites, such as milky red areas, peripheral light brown structureless areas and linear irregular vessels. These features, asymmetric pigmented follicles and at RCM >= 3 atypical cells in five fields and focal follicular extension of atypical cells at DEJ may help in recognizing AHLM/LMM even when LM conventional features (e.g., obliteration of hair follicles under dermoscopy and large pagetoid cells under RCM) are absent or present only in very small areas of the lesion.

Trichilemmal carcinoma is a rare cutaneous tumor with a frequently good prognosis but without standard criteria for surgical treatment. We aimed to show the results of a two-stage surgical approach that preserves the anatomical features of the ear. We report a case of 82-year-old man with trichilemmal carcinoma of the ear that was treated with a two-stage surgical approach. We observed that 5 months after the surgeries, the ear appeared entirely healed and there were no signs of recurrence; hence, our two-stage surgical approach allowed the anatomy of the ear to be preserved after the complete excision of the tumor.

BackgroundSystemic Sclerosis (SSc) is a connective tissue disease characterized by microvascular dysfunction, abnormal fibroblast activation and antibodies production, with cutaneous and visceral involvement. Hand-related manifestations include sclerosis, loss of elasticity, sclerodactyly, painful digital ulcers, atrophy, and gangrene. Autologous fat grafting is based on the implantation of adipose-derived stem cell (ADSCs) which have demonstrated to have pro-angiogenic, anti-inflammatory, regenerative, and immunosuppressive properties. This technique, combined with bone shaving, is believed to be effective in avoiding finger amputation in SSc-patients affected by digital gangrene.ObjectivesEvaluate our experience with the use of autologous fat grafting and bone shaving for the treatment of digital necrosis in patients affected by SSc.MethodsAccording to our schedule, we treated 7 female SSc patients with digital gangrene and exposed bone at the fingertips, enrolled in our University Hospital from March 2018 to January 2020. Digital gangrene was treated by a combination of bone shaving and autologous fat grafting in order to avoid amputation. During the bone shaving, necrotic tissue was removed until bone bleeding was obtained. This procedure could be repeated by trained rheumatologists every 2 weeks in our Clinic. The aim of this repeated debridement was to promote the progression of the granulation tissue inside the dead tissue of the finger. Autologous fat grafting consists of a surgical procedure of ADSCs implantation at the base of the finger. It is performed in order to empower the neurovascular bundle and improve tissue healing. This treatment could be performed every 3 months by trained plastic surgeons. The combination of these two techniques allows the maximum finger length preservation.ResultsComplete healing of all fingers was achieved in 6-12 months by performing bone shaving every 2 weeks and 2 treatments of autologous fat grafting. Results have proved to be long-lasting. At 1-year follow-up, patients did not present any recurrence. Every procedure was performed under local anaesthesia and appropriate analgesic therapy. A high degree of compliance and satisfaction of all patients was noted.ConclusionFinger amputation in Systemic Sclerosis should be avoided. This traumatic surgical procedure is responsible for microvascular damages worsening SSc-related vasculopathy. Stump ulcers often occurs and wound healing usually takes place by secondary intention. In our experience, the combination of bone shaving and autologous fat grafting has proven to be effective and safe in preserving the maximum amount of viable tissue and obtaining a long-lasting result in treated SSc patients.Disclosure of InterestsNone declared

BackgroundSystemic Sclerosis (SSc) is a life-threatening connective tissue disease characterized by endothelial dysfunction, autoimmune abnormalities and aberrant fibrosis. Several reports showed an increased risk of cancer in SSc compared to general population, including breast cancer (BC). The relationship between BC and SSc has long been discussed with contradictory results. In our recent Sclero-Breast study we analyzed clinical-pathological features of BC in SSc; we finally observed the development of BC with early stages and good prognosis among these patients.ObjectivesThe aim of this project was to explore the immunohistochemical (IHC) expression of potential biomarkers involved in the molecular pathways at the basis of SSc and BC etiophatogenesis as update analysis from the Sclero-Breast study.MethodsOur observational multicenter retrospective study, performed at Modena University Hospital and Reggio Emilia Hospital in northern Italy, enrolled 33 SSc women with a personal history of BC between January 2017 and December 2019. Clinical and pathological characteristics of BC and SSc were collected. For 22 patients, BC tissues were available and IHC analysis was performed using specific antibodies to evaluate biomarkers and pathways potentially involved. The antibodies used included: PI3K/mTOR/TGFβ/PDGFRα/PDGFRβ/VEGF/EGFR/IL-6/CTLA-4/PDL1. We also reported TILs percentage (stromal tumor-infiltrating lymphocytes) of each sample. The following scores were assigned for general IHC analysis: (-) negative, (1+) positive tumor cells 50%. For PDL1 we considered a positivity in case of PD-L1 expression ≥1% in infiltrating inflammatory cells. For TILs quantification we applied the score: 0 (negative), ≤ 50% (low-median expression), >50% (high expression).ResultsThe first IHC analysis was performed on the samples of invasive BC patients (20 pts) and showed a prevalence of high PI3K expression (score of 3+ in 55% of cases) with mTOR overexpression in 45%. A PDL1 positivity was detected in 30%, with high TILs expression in 30%. Biopsies from the 2 pts with ductal carcinoma in situ were characterized by a negativity of almost all parameters, except for a medium-high TILs expression reported (40%/90% respectively). See Figure 1. IHC analysis was also performed according to BC subtypes. The group of HR+/HER2 negative showed high PI3K expression (score 3+) in most of cases (59%) with mTOR overexpression in 50%. CTLA-4 and PDL1 were positive in 25%, with high TILs expression in 25%. HER2 positive patients showed a high PI3K positivity in 50% of cases with mTOR positivity (score 3+) in 25% and high TGFβ expression (score 3+) in 25%. PDL1 was positive in 50% with high TILs expression in 25%. In Triple Negative group, PI3K overexpression was found in 75% of pts with half of cases represented by mTOR score 3+. PDL1 was positive in 50% with high TILs representation (80% of total cell count) in 50% of pts.Figure 1.IHC analysis and TILs% expression in histological samples of SSc patients with invasive BC.ConclusionAccording to our results, SSc patients with BC showed high positivity for PDL1 and high TILs representations in all subtypes. Furthermore, the high expression of PI3K, did not always correlate with mTOR overexpression. Further investigations on larger numbers are needed; however, these aspects seem to confirm that SSc subjects might develop BC at good prognosis, suggesting again a de-escalation strategy of cancer therapies. Finally, the possibility to personalize oncological targeted treatments in this subset of fragile patients could be promising.Disclosure of InterestsNone declared

The present article reports the case of a patient subjected to polyacrylamide polymers-composed gel cutaneous infiltration in the penis for cosmetic purposes, resulting in severe invalidating outcomes. A significant tissue reaction to the subcutaneous injection of polyacrylamide gel for the penis enlargement purpose resulted in permanent and invalidating scars both on the esthetic and functional levels. Such a result must be plainly be taken into account both singly and in the light of the international literature to exclude this method as standard uroandrologic activity.

Alcuni manuali usano riquadri incorniciati, eventualmente estesi su più pagine, per separare dal testo principale materiale a carattere avanzato o di altro tipo. Il pacchetto longmedal si propone di fornire un metodo semplice per riprodurre questo tipo di oggetti in un documento prodotto con LATEX.

Intense Saharan dust deposition occurs over large oligotrophic areas in the Mediterranean Sea and in the Tropical Atlantic, and its impact on the biogeochemical functioning of such oligotrophic ecosystems needs to be understood. However, due to the logistical difficulties of investigating in situ natural dust events, and due to the inherent limitations of microcosm laboratory experiments, new experimental approaches need to be developed. In this paper, we present a new experimental setup based on large, clean mesocoms deployed in the frame of the DUNE (a DUst experiment in a low-Nutrient, low-chlorophyll Ecosystem) project. We demonstrate that these tools are highly relevant and provide a powerful new strategy to in situ studies of the response of an oligotrophic ecosystem to chemical forcing by atmospheric deposition of African dust. First, we describe how to cope with the large amount of dust aerosol needed to conduct the seeding experiments by producing an analogue from soil collected in a source area and by performing subsequent appropriate physico-chemical treatments in the laboratory, including an eventual processing by simulated cloud water. The comparison of the physico-chemical characteristics of produced dust analogues with the literature confirms that our experimental simulations are representative of dust, aging during atmospheric transport, and subsequent deposition to the Mediterranean. Second, we demonstrate the feasibility in coastal areas to installing, in situ, a series of large (6 × 52 m3) mesocosms without perturbing the local ecosystem. The setup, containing no metallic parts and with the least possible induced perturbation during the sampling sequence, provides an approach for working with the required conditions for biogeochemical studies in oligotrophic environments, where nutrient and micronutrients are at nano- or subnano-molar levels. Two, distinct "seeding experiments" were conducted by deploying three mesocosms serving as controls (CONTROLS-Meso = no addition) and three mesocosms seeded with the same amount of Saharan dust (DUST-Meso = 10 g m−2 of sprayed dust). A large panel of biogeochemical parameters was measured at 0.1 m, at 5 m and 10 m in all of the mesocosms and at a selected site outside the mesocosms before seeding and at regular intervals afterward. Statistical analyses of the results show that data from three mesocosms that received the same treatment are highly reproducible (variability < 30%) and that there is no significant difference between data obtained from CONTROLS-Meso and data obtained outside the mesocosms. This paper demonstrates that the methodology developed in the DUNE project is suitable to quantifying and parameterizing the impact of atmospheric chemical forcing in a low-nutrient, low-chlorophyll (LNLC) ecosystem. Such large mesocosms can be considered as 1-D ecosystems so that the parameterization obtained from these experiments can be integrated into ecosystem models.

The population dynamic of the Colorado beetle (Leptinotarsa decemlineata Say) was studied in Central Italy in 1987–1988 to establish an economic threshold for its control. Statistical analysis allowed a measure of damage done at each stage of development of the pest to be expressed in terms of “day-individuals”. On the basis of the data it is possible to predict that, starting from a density of 1 egg mass per plant, a consequent mean density of 24 L4 it can be expected, that this is a level able to cause about a 50 % production decrease. To have a rational margin of recovery, a threshold of 25 egg masses on 50 plants/ha sampled in the third and fourth week of May is suggested. Zusammenfassung Zur Populationsdynamik und zum wirtschaftlichen Schwellenwert des Kartoffelblattkafers, Leptinotarsa decemlineata (Say) (Col., Chrysomelidae), in Mittelitalien Die Populationsdynamik von Leptinotarsa decemlineata (Say) wurde in den Jahren 1987–1988 in Mittelitalien mit der Zielsetzung untersucht, einen wirtschaftlichen Schwellenwert fur seine Kontrolle festzulegen. Statistische Analysen erlaubten eine Messung der Schaden wahrend jeder Entwicklungsstufe des Befalls, die als “Insektenfras pro Tag” ausgedruckt werden. Auf der Basis der ermittelten Daten ist es moglich, ausgehend von einem Eigelege pro Pflanze, vorherzusagen, das ein durchschnittlicher Befall von 24 L4 erwartet werden kann, d. h. ein Wert, der eine Produktionsverringerung von 50 % zur Folge haben konnte. Um eine rationelle Wiedergewinnungsquote zu haben, sollte mit der Behandlung begonnen werden, wenn in der 3. und 4. Maiwoche mehr als 25 Eigelege auf 50 Pflanzen/ha festgestellt werden.

This study of sleep changes in patients with cluster headache (CH) was conducted in view of the nocturnal predominance of this condition, the efficacy of oxygen and the fact that the attacks follow oxygen desaturation. Proposed mechanisms include impairment of carotid body activity secondary to hypothalamic vasomotor regulatory dysfunction. Sixteen patients with episodic CH and 29 healthy volunteers underwent nocturnal polysomnography. Five (31.3%) patients with episodic CH were found to have sleep apnoea (SA). Two patients with SA experienced two attacks during the study period. The attacks followed episodes of oxygen desaturation and were associated with REM sleep. In two patients with SA and CH, treatment with continuous positive airway pressure abolished their oxygen desaturation, sleep apnoeas and headaches. Our study confirmed the high percentage of CH associated with SA. We suggest that oxygen desaturation may be a trigger factor in some patients and play a role in the pathogenesis of CH.

Aggressive non-Hodgkin lymphomas (NHL), such as Diffuse Large B cell lymphoma (DLBCL) and mantle cell lymphoma (MCL), are one of a small number of important human cancers increasing in incidence in the US over the last four decades. Although these lymphomas are now potentially curable, almost half the treated patients still develop relapsed/refractory disease with poor survival outcomes, indicating an urgent need for better therapeutic approaches with improved efficacy. Double–hit lymphomas (DHL) constitute a particularly aggressive subtype of DLBCL and are characterized by a chromosomal breakpoint affecting the MYC/8q24 locus in combination with another recurrent breakpoint, usually a t(14;18)(q32;q21) involving BCL2. Prognosis for DHL is extremely poor, indicating a need for new treatment options as well. Multi-drug combination therapies are expected to potentiate therapeutic responses and delay disease recurrence by blocking adaptive resistance responses. Carfilzomib (CFZ), a novel second-generation proteasome inhibitor, and the novel Selective Inhibitor of Nuclear Exports (SINE) KPT-330 are effective treatments for refractory lymphomas. We hypothesized that combining the two would be even more successful because the drugs target different cellular pathways and processes in malignant B-cells. CFZ inhibits chymotrypsin-like, protein-degrading activity in the ubiquitin-proteasome pathway while KPT-330 irreversibly inhibits the major nuclear export receptor, chromosome region maintenance 1, CRM1, also termed XPO1. This study investigates whether the effects of CFZ and KPT-330 in combination are synergistic and thus more effective, reducing side effects and chemoresistance. Two DLBCL cell lines, DOHH-2 and OCI-Ly10, two DH-DLBCL cell lines, CJ and U-2973, and two MCL cell lines, Mino and Jeko-1, were used. Working with these cell lines, we identified and analyzed the increase in the efficacy of the combination over single agents alone through MTS proliferation and Annexin-V binding apoptosis assays. Growth inhibitory combination indexes for each cell line were calculated, and the Chou-Talalay Method was used to quantify additive effects (CI=1), synergistic effects (CI1). Results indicated strong synergistic behavior of the combinatorial therapy, with many of the dose combinations indexes falling below 1. Apoptosis assays also showed a high degree of synergy when combining CFZ with KPT-330. The efficacy of CFZ and KPT-330 in combination signifies the combination’s potential as a foundation for future studies, treatments, and clinical trials. Disclosures: Kirk: Onyx Pharmaceuticals: Employment, Equity Ownership. Kauffman:Karyopharm Therapeutics Inc.: Employment. Shacham:Karyopharm : Employment, Equity Ownership, Membership on an entity’s Board of Directors or advisory committees, Patents & Royalties.

The biological significance of the ubiquitin-proteasome system in the control of cellular processes has been well-recognized; however, the pathophysiological importance of the immunoproteasome (i-proteasome), the inducible form of the proteasome, has not been well-appreciated in cancer cells, particularly in mantle cell lymphoma (MCL), a clinically challenging, aggressive B-cell non-Hodgkin’s lymphoma (NHL-B). The proteasome activity is regulated by standard catalytic subunits β1, β2 and β5, or inducible catalytic subunits LMP2 (β1i), MECL-1 (β2i), and LPM7 (β5i). The inducible catalytic subunits have been reported to be highly expressed in hematological malignancies. Our results indicated that inducible catalytic subunits of i-proteasome are highly expressed in both established and primary MCL cells. Interestingly, we found that the expression of i-proteasome subunits were required for the anti-MCL activity of carfilzomib, a novel second-generation proteasome inhibitor, in MCL cells. Both primary and established MCL cells with high expression of i-proteasome subunits were more responsive to carfilzomib, even at low dose treatment (IC50, between 1.2nM to 8.6nM). In contrast, MCL cells with low/no expression of i-proteasome subunits are highly resistant to carfilzomib (IC50 >200 nM). These results suggested that the i-proteasome could play an important role in determining the sensitivity of carfilzomib. To elucidate the mechanism responsible for carfilzomib sensitivity in MCL cells, we used IFN-γ to stimulate carfilzomib-resistant MCL cell line Rec-1, which lacked the expression of i-proteasome subunits especially LMP2. We found that pretreatment of Rec-1 cells with IFN-γ for 48 hours increased i-proteasome subunit LMP2 but not c-proteasome subunit b1, and led to sensitization of Rec-1 cells to carfilzomib. To provide direct evidence that upregulation of i-proteasome subunit LMP2 by IFN-γ was responsible for the observed carfilzomib sensitization, siRNA downregulation of LMP2 was applied prior to exposure to IFN-γ. After LMP2 knockdown, carfilzomib sensitization was attenuated. The data show that an intact i-proteasome, especially LMP2, appears to be necessary for its anti-MCL activity, suggesting that i-proteasome could serve as a biomarker for identifying patients who will benefit from carfilzomib. Since bruton’s tyrosine kinase (Btk) is pivotal for B-cell lymphoma growth and its downstream signals are associated with NF-κB and other important survival pathways, we combined ibrutinib, a novel Btk inhibitor, with carfilzomib for treatment of MCL cells. We found that ibrutinib sensitized carfilzomib-resistant MCL cells, and overcame carfilzomib resistance in these cells. Taken together, i-proteasome could be indispensable for the action of carfilzomib in MCL cells. However, ibrutinib overcame carfilzomib resistance in MCL cells indicating ibrutinib has different therapeutic targets that are not associated with i-proteasome. Our data could demonstrate the profound potential of using an ibrutinib and carfilzomib combination in clinical trials for patients with relapsed or refractory MCL. Disclosures: No relevant conflicts of interest to declare.

Diffuse large B-cell lymphoma (DLBCL) is the most common lymphoid malignancy in adults; in the United States alone 30,000 new cases are diagnosed every year. Approximately 5% of DLBCLs are double-hit lymphomas (DHL), a recently discovered subtype of lymphoma defined by a chromosomal translocation and subsequent breakpoint at the MYC/8q24 loci in combination with another recurrent breakpoint, usually BCL2/18q21 or BCL6/3q27. DHL is resistant to virtually all therapeutic drugs and chemotherapy, showing extremely poor prognosis even with an R-CHOP regimen. Currently, there is no known therapeutic strategy that can effectively treat double-hit lymphomas. Lack of clinically relevant human experimental models for understanding the molecular biologic and genetic basis of DHL continues to hamper identification of valid therapeutic targets for development of effective therapy. However, we have developed two unique DH-DLBCL cell lines (CJ and RC), harboring both MYC and BCL2 translocations. These cell lines display the morphologic, immunophenotypic, genotypic, and biologic characteristics of the lymphoma cells present in the original diagnostic specimen. We have also obtained another BCL2/MYC DL-DLBCL cell line, U-2973, recently established from another research institution (Uppsala University, Sweden). Together, these DHL cell lines will be useful experimental models for in vitro and in vivo studies of DH-DLBCL pathogenesis and therapeutics. Recent clinical findings have demonstrated that the novel second-generation proteasome inhibitor, carfilzomib (CFZ), and the Btk inhibitor, ibruitinib (IBR), as single agents have shown promising results in relapsed/refractory hematologic malignancies. In our initial experiments, we examined the efficacy of using CFZ and IBR in combination in three DH-DLBCL cell lines using proliferation MTT assays. CJ and U-2973 cells were moderately resistant to IBR (IC50>20 uM) and were highly sensitive to CFZ (IC50=2.5-10 nM) in comparison to RC cells that were sensitive to both IBR (5-10 uM) and CFZ (5-10 nM). When combined, these drugs exhibited strong synergism, particularly in CJ cells, with combination indexes Disclosures: Kirk: Onyx Pharmaceuticals: Employment, Equity Ownership.

The incidence of diffuse large B-cell lymphoma (DLBCL) is rising, a situation that highlights the need for improved therapy with greater efficacy and fewer side effects. The fundamental clinical problem is that standard frontline combination chemotherapy for DLBCL (R-CHOP) achieves lasting remissions but is not curative. Development of a new, effective, low-toxicity frontline therapy against DLBCL that incorporates targeted agents is much needed. Constitutive activation of the NF-kB, NFAT, and STAT3 (NNS) pathways is a hallmark of DLBCL, particularly the activated B-cell–like (ABC) subtype. Although these pathways have been studied intensively recently, the precise mechanisms controlling these pathways in DLBCL is still uncertain. Elucidating the key mechanism(s) controlling these pathways should improve our understanding of the pathophysiology of DLBCL as well as the therapeutic strategy against this deadly disease. MicroRNAs (miRNA) are short 18-23 nucleotide long noncoding RNAs that posttranscriptionally regulate gene expression by binding to mRNA. Aberrant expression of miRNAs has been implicated in numerous diseases, including cancers. MiRNA-155 (miR- 155) has shown to be overexpressed in aggressive hematologic malignancies, including DLBCL. The oncogenic nature of this miRNA was confirmed in Em-miR-155 transgenic mice, where the mice develop aggressive pre B cell neoplasms within 3-4 weeks. However, the role miR-155 in the pathophysiology of DLBCL is still unclear. We performed gene expression profiling (GEP) in 24 representative DLBCL cell lines (17 GCB- and 7 ABC-subtype). Our data show that miR-155 expression is significantly higher in ABC vs. GCB DLBCL cell lines (p-value Disclosures: No relevant conflicts of interest to declare.

Mantle cell lymphoma (MCL) is a clinically challenging, usually aggressive B-cell non-Hodgkin’s lymphoma (NHL-B) showing hyperactive, autonomously growing neoplastic B cells with extended tumor cell survival, demonstrate wide-spread chemokine-mediated lymphoma cell migration and homing into lymphoid tissue with poorly-characterized chemo-resistance. Recent introduction of molecularly targeted therapies, such as targeting the Bruton’s tyrosine kinase (BTK) in B-cell receptor (BCR) pathway with ibrutinib revealed significant advances in the treatment of this disease. Ibrutinib was shown to completely and irreversibly inhibit B-cell activation and block signaling downstream of BTK. In this study we have examined the pathophysiological significance of targeting BTK with ibrutinib in MCL cells. Our initial findings showed that STAT3 is constitutively activated in MCL cells and ibrutinib, even at low drug concentration, can effectively down-regulate both phospho-STAT3 (pSTAT3) and NF-κB activation, two key pathways involved in MCL growth/survival (G/S). To confirm the direct target effect of BTK, we employed siRNA that specifically targets BTK. Our results revealed that BTK knock-down in MCL cells lead to a significant reduction of pSTAT3 and inhibition of the NF-κB pathway. Recent studies have indicated that transcription factor STAT3 has emerged as an important regulator of MicroRNAs (miRNAs) and STAT3 signaling pathways are also controlled by distinct miRNAs. microRNA-155 (miR-155) is an oncogenic microRNA that is frequently up-regulated in B-cell lymphoproliferative disorders including MCL. Activating the BCR pathway leads to miR-155 activation and down-regulation of SOCS1, a negative regulator of both STAT3 and NF-κB. To investigate the role of miR-155 in the activation of STAT3 and NF-kB in MCL, we inhibited miR-155 expression in MCL cells by transiently transfecting an anti-miR155 into MCL cells. Our results indicated that inhibition of miR-155 suppresses STAT3 and NF-kB activation, leading to cell growth inhibition as well as reducing MCL cellular migration. Our data also showed that the BTK inhibitor ibrutinib can moderately down regulate miR-155 expression, an effect similar to the direct knock-down of BTK using siRNA, suggested that miR-155 may, at least in part, play a role in the regulation of STAT3 by BCR. Next, we utilized an in vivo hu-SCID MCL mouse model to test the effect of ibrutinib on the BTK-miR-155 pathway. Consistent with clinical observation, ibrutinib compartmentally shifted MCL cells from the lymphoid tissue into the peripheral blood, leading to MCL cytotoxicity and extending SCID mouse survival, and down-regulated pSTAT3 activities. Our data indicated that the BTK- STAT3 pathway is a critical mechanism for growth and survival in MCL, A better understanding of the complex regulatory networks between BCR and STAT3 may lead to better therapeutic efficacy in MCL. Disclosures: No relevant conflicts of interest to declare.

This study reports some data from periodic surveys of vegetation in a typical Umbrian olive grove (Central Italy) over a two-year period, 1983–84. The descriptive analysis of the data shows that: — the insect population present on leaves is always higher than that on twigs; — the ratio between the number of living and dead insects increases with the age of the coccid even if the ratio depends on how long the coccid remains in a particular instar or stage of development; — the extent of parasitization was rather modest; — the insect winters mainly in the form of 3rd instar larva or, less frequently, as 2nd instar larva or young female. A statistical model was formulated based on the assumption of constant birth, mortality and drop rates between two successive surveys. This model can be used to estimate the extent of the birth, mortality and drop rate in a sample unit of vegetation. In particular the application of the above model showed that: — mortality is highest for 1st instar larvae and it is associated with periods marked by high temperature; — the extent of drops increases with instar stage and is most intense in the rainy periods. Zusammenfassung Zur Populationsdynamik von Saissetia oleae (Oliv.) (Homoptera, Coccidae) auf Olivenbaumen Die vorliegende Studie stutzt sich auf Daten, die mittels periodischer Stichprobenentnahmen in einem typisch umbrischen Olivenhain (Mittelitalien) in den Jahren 1983/84 gewonnen wurden. Die Analyse der Daten ergab: — die Population auf den Blattern war immer groser als die auf den Zweigen; — das Verhaltnis Lebende/Tote wuchs im Verhaltnis zum Larven- und Entwicklungsstadium der Kokzidien, auch wenn es von der Verbleibdauer derselben im entsprechenden Stadium abhing; — das Ausmas des Befalls erwies sich als recht gering; es uberwinterten hauptsachlich die Larven III, gefolgt von den Larven II und den jungen Weibchen. Es wurde ein statistisches Modell erstellt, das sich auf in regelmasigem Abstand zueinander stehende Geburts-, Sterbe- und Loslosungsraten zwischen zwei aufeinander folgenden Kontrollen stutzt, und das dazu benutzt werden kann, die Vermehrung, die Sterblichkeit und das Loslosen einer Versuchseinheit zu schatzen. Die Anwendung des Modells hat insbesondere ergeben: — die Sterblichkeit war am hochsten fur die Larven I; das galt besonders fur die Zeiten mit hohen Temperaturen; — das Ausmas der Loslosungen wuchs mit dem Typ des Larvenstadiums; ganz besonders gros war es in regenreichen Zeiten.

The life-cycle of T. ampelophaga has been observed in 3 vineyards in Umbria (Central Italy) for 9 years (1976–1984) in the field and in the laboratory in order to compare the results of both. A summary is also given on world distribution, of this insect and in particular have been studied natural enemies and abiotic factors (meteorological and summer spraying), which are supposed to be dangerous to this insect. The results show the following: - the insect has only one generation per year and overwintering takes place in the bark of the vine and in stubs as larvae of second instar; - six species of parasites were found, that is 2 Chalcididae (Brachymeria intermedia Nees and Hocheria unicolor Walk.), 1 Braconidae (Apanteles ultor Reinh.), 2 Tachinidae (Zenillia libatrix [Panzer] and Exorista sp.) and 1 Trichogrammatidae (Trichogramma evanescens Westw.). The percentage of parasites is not very high so that they are not able to control the infestation of T. ampelophaga; — rainfalls, winds and high temperatures kill the pre-adult instar of T. ampelophaga but fungicide and insecticide commonly sprayed in summer are more dangerous for the insect than the previous ones. Zusammenfassung Beitrage zur Biologie und zum Massenwechsel von Theresimima ampelophaga Bayle-Barelle (Lep., Zygaenidae) Es wurden Biologie und Ethologie von T. ampelophaga sowie die klimatischen Faktoren hinsicht-lich der Sterblichkeit der larvalen Stadien dieser Art in 3 verschiedenen Weinbergen (Mittelitalien) von 1976-1984 untersucht. Es konnte gezeigt werden, das T. ampelophaga jahrlich eine Generation bildete, deren Larven im 2. Stadium unter der Baumrinde und am Sporn der Schnittstellen des vergangenen Jahres uberwinterte. Die Forschungen uber T. ampelophaga ergaben 6 Arten von naturlichen Feinden der Eier, Larven und Puppen, die wegen ihrer geringen Dichte jedoch kein wesentliches Element zur Reduktion von T. ampelophaga bildeten. Die 6 Arten sind: Tricho-gramma evanescens Westw. (Hym., Trichogrammatidae), Brachymeria intermedia Nees und Hocheria unicolor Walk. (Hym., Chalcididae), Apanteles ultor Reinh. (Hym., Braconidae). Zenillia libatrix (Panzer) und Exorista sp. (Dipt., Tachinidae). Die wichtigsten Faktoren, die den Befall durch T. ampelophaga verminderten, waren hohe Temperaturen, Regen und Wind sowie Fungizid- und Insektizid-Ausbringungen in den Weinbergen.

This study speaks about the relationship between olive fly (D. oleae) ovipositing and certain physical parameters of drupes. During the first period of observation weight was the most important parameter statistically. Subsequently, this relationship became less important because of the remarcable increase in the density of population and because of the presence in the olives of particular substances which induce the female to select the smaller drupes for ovipositing. Zusammenfassung Verteilung des Befalls mit Dacus oleae (Gmel.) (Diptera, Tephrytidae) bei Oliven In dieser Studie sind die Ergebnisse eines Experiments zusammengefast, das in einem Jahr hohen Befalls von D. oleae (1983) und in 2 verschiedenen Olivenhainen Mittelitaliens die Beziehung zwischen der Anzahl der Eiablagen in einer Steinfrucht und einigen ihrer physikalischen Parameter untersuchte. Die Ergebnisse zeigten sehr deutlich, das von alien betrachteten Variablen der Steinfrucht (Gewicht, Lange der groml;sen und der kleinsten Achse, Sorte sowie Lage und Zeitpunkt der Pflanzung) das Gewicht die Veranderlichkeit der Eiablagen in den Steinfruchten statistisch am besten erklart. Diese Abhangigkeit schwacht sich mit der Zeit ab, nicht nur auf Grund der Erhoml;hung des Befalls, sondern vor allem auf Grund der Zusammensetzung der anziehenden und abstosenden Substanzen, die wahrend des Reifungsprozesses von den Oliven produziert werden. Ein weiteres Resultat ist, das schwerere Steinfruchte, obwohl sie im Durchschnitt mehr als eine Eiablage aufweisen, die vollstandige Entwicklung des Nachwuchses besser garantieren als leich-tere.

n/a

n/a