IMpassion132 double-blind randomised phase III trial of chemotherapy with or without atezolizumab for early relapsing unresectable locally advanced or metastatic triple-negative breast cancer.

BACKGROUND: Immune checkpoint inhibitors improve the efficacy of first-line chemotherapy for patients with programmed death-ligand 1 (PD-L1)-positive unresectable locally advanced/metastatic triple-negative breast cancer (aTNBC), but randomised data in rapidly relapsing aTNBC are scarce. PATIENTS AND METHODS: IMpassion132 (NCT03371017) enrolled patients with aTNBC relapsing <12 months after last chemotherapy dose (anthracycline and taxane required) or surgery for early TNBC. PD-L1 status was centrally assessed using SP142 before randomisation. Initially patients were enrolled irrespective of PD-L1 status. From August 2019, enrolment was restricted to PD-L1-positive (tumour immune cell ≥1%) aTNBC. Patients were randomised 1:1 to placebo or atezolizumab 1200 mg every 21 days with investigator-selected chemotherapy until disease progression or unacceptable toxicity. Stratification factors were chemotherapy regimen (carboplatin plus gemcitabine or capecitabine monotherapy), visceral (lung and/or liver) metastases and (initially) PD-L1 status. The primary endpoint was overall survival (OS), tested hierarchically in patients with PD-L1-positive tumours and then, if positive, in the modified intent-to-treat (mITT) population (all-comer patients randomised pre-August 2019). Secondary endpoints included progression-free survival (PFS), objective response rate (ORR) and safety. RESULTS: Among 354 patients with rapidly relapsing PD-L1-positive aTNBC, 68% had a disease-free interval of <6 months and 73% received carboplatin/gemcitabine. The OS hazard ratio was 0.93 (95% confidence interval 0.73-1.20, P = 0.59; median 11.2 months with placebo versus 12.1 months with atezolizumab). mITT and subgroup results were consistent. Median PFS was 4 months across treatment arms and populations. ORRs were 28% with placebo versus 40% with atezolizumab. Adverse events (predominantly haematological) were similar between arms and as expected with atezolizumab plus carboplatin/gemcitabine or capecitabine following recent chemotherapy exposure. CONCLUSIONS: OS, which is dismal in patients with TNBC relapsing within <12 months, was not improved by adding atezolizumab to chemotherapy. A biology-based definition of intrinsic resistance to immunotherapy in aTNBC is urgently needed to develop novel therapies for these patients in next-generation clinical trials.

Pathologic complete response (pCR) to neoadjuvant treatment with or without atezolizumab in triple-negative, early high-risk and locally advanced breast cancer: NeoTRIP Michelangelo randomized study.

BACKGROUND: High-risk triple-negative breast cancers (TNBCs) are characterized by poor prognosis, rapid progression to metastatic stage and onset of resistance to chemotherapy, thus representing an area in need of new therapeutic approaches. Programmed death-ligand 1 (PD-L1) expression is an adaptive mechanism of tumour resistance to tumour-infiltrating lymphocytes, which in turn are needed for response to chemotherapy. Overall, available data support the concept that blockade of PD-L1/programmed cell death protein 1 checkpoint may improve efficacy of classical chemotherapy. PATIENTS AND METHODS: Two hundred and eighty patients with TNBC were enrolled in this multicentre study (NCT002620280) and randomized to neoadjuvant carboplatin area under the curve 2 and nab-paclitaxel 125 mg/m2 intravenously (i.v.) on days 1 and 8, without (n = 142) or with (n = 138) atezolizumab 1200 mg i.v. on day 1. Both regimens were given q3 weeks for eight cycles before surgery followed by four cycles of an adjuvant anthracycline regimen. The primary aim of the study was to compare event-free survival (EFS), and an important secondary aim was the rate of pathological complete response (pCR defined as the absence of invasive cells in breast and lymph nodes). The primary population for all efficacy endpoints is the intention-to-treat (ITT) population. RESULTS: The ITT analysis revealed that pCR rate after treatment with atezolizumab (48.6%) did not reach statistical significance compared to no atezolizumab [44.4%: odds ratio (OR) 1.18; 95% confidence interval 0.74-1.89; P = 0.48]. Treatment-related adverse events were similar with either regimen except for a significantly higher overall incidence of serious adverse events and liver transaminase abnormalities with atezolizumab. CONCLUSIONS: The addition of atezolizumab to nab-paclitaxel and carboplatin did not significantly increase the rate of pCR in women with TNBC. In multivariate analysis, the presence of PD-L1 expression was the most significant factor influencing the rate of pCR (OR 2.08). Continuing follow-up for the EFS is ongoing, and molecular studies are under way.

Immunological differences between primary and metastatic breast cancer.

Background: Little is known about how the immune microenvironment of breast cancer evolves during disease progression. Patients and methods: We compared tumor infiltrating lymphocyte (TIL) count, programmed death-ligand 1 (PD-L1) protein expression by immunohistochemistry and mRNA levels of 730 immune-related genes using Nanostring technology in primary and metastatic cancer samples. Results: TIL counts and PD-L1 positivity were significantly lower in metastases. Immune cell metagenes corresponding to CD8, T-helper, T-reg, Cytotoxic T, Dendritic and Mastoid cells, and expression of 13 of 29 immuno-oncology therapeutic targets in clinical development including PD1, PD-L1, and CTLA4 were significantly lower in metastases. There was also coordinated down regulation of chemoattractant ligand/receptor pairs (CCL19/CCR7, CXCL9/CXCR3, IL15/IL15R), interferon regulated genes (STAT1, IRF-1,-4,-7, IFI-27,-35), granzyme/granulysin, MHC class I and immune proteasome (PSMB-8,-9,-10) expression in metastases. Immunotherapy response predictive signatures were also lower. The expression of macrophage markers (CD163, CCL2/CCR2, CSF1/CSFR1, CXCR4/CXCL12), protumorigenic toll-like receptor pathway genes (CD14/TLR-1,-2,-4,-5,-6/MyD88), HLA-E, ecto-nuclease CD73/NT5E and inhibitory complement receptors (CD-59,-55,-46) remained high in metastases and represent potential therapeutic targets. Conclusions: Metastatic breast cancers are immunologically more inert than the corresponding primary tumors but some immune-oncology targets and macrophage and angiogenesis signatures show preserved expression and suggest therapeutic combinations for clinical testing.

Immune modulation of pathologic complete response after neoadjuvant HER2-directed therapies in the NeoSphere trial.

BACKGROUND: To investigate in the NeoSphere trial the contribution of the immune system to pathologic complete response in the breast (pCRB) after neoadjuvant docetaxel with trastuzumab (TH), pertuzumab (TP), or both (THP), or monoclonal antibodies alone (HP). PATIENTS AND METHODS: Immune gene mRNA expression (n = 350, 83.8%), lymphocyte infiltration (TIL, n = 243, 58.3%), and PDL1 by immunohistochemistry (n = 305, 73.1%) were correlated with pCRB. We studied five selected genes (IFNG, PD1, PDL1, PDL2, CTLA4) and six immune metagenes corresponding to plasma cells (IGG), T cells (CD8A), antigen-presenting cells (MHC2), and to MHC1 genes (MHC1), STAT1 co-expressed genes (STAT1), and interferon-inducible genes (IF-I). Gene expression data from the NOAH trial were used for validation. RESULTS: TIL as continuous variable and PDL1 protein expression were not significantly associated with pCRB. Expression of immune genes/metagenes had different association with pCRB after THP than after other therapies. With THP, higher expression of PD1 and STAT1, or any among PDL1, CTLA4, MHC1, and IF-I were linked with lower pCRB. In the combined TH/TP/HP treatment group, in multivariate analysis, higher expression of PD1, MHC2, and STAT1 were linked with pCRB, and higher PDL1, MHC1, or IF-I to lower pCRB. In the NOAH, a similar association of higher STAT1 with higher pCRB, and higher MHC1 and IF-I with lower pCRB was found for trastuzumab/chemotherapy but not for chemotherapy treatment only. CONCLUSIONS: The immune system modulates response to therapies containing trastuzumab and pertuzumab. Greatest benefit from THP is observed for low expression of some immune markers (i.e. MHC1, CTLA4). The involvement of PDL1 in resistance supports testing combinations of HER2-directed antibodies and immune-checkpoint inhibitors.

Optimizing choices and sequences in the diagnostic-therapeutic landscape of advanced triple-negative breast cancer: An Italian consensus paper and critical review.

Triple-negative (TN) metastatic breast cancer (mBC) represents the most challenging scenario withing mBC framework, and it has been only slightly affected by the tremendous advancements in terms of drug availability and survival prolongation we have witnessed in the last years for advanced disease. However, although chemotherapy still represents the mainstay of TN mBC management, in the past years, several novel effective agents have been developed and made available in the clinical practice setting. Within this framework, a panel composed of a scientific board of 17 internationally recognized breast oncologists and 42 oncologists working within local spoke centers, addressed 26 high-priority statements, including grey areas, regarding the management of TN mBC. A structured methodology based on a modified Delphi approach to administer the survey and the Nominal Group Technique to capture perceptions and preferences on the management of TN mBC within the Italian Oncology community were adopted. The Panel produced a set of prioritized considerations/consensus statements reflecting the Panel position on diagnostic and staging approach, first-line and second-line treatments of PD-L1-positive/germline BRCA (gBRCA) wild-type, PD-L1-positive/gBRCA mutated, PD-L1-negative/gBRCA wild-type and PD-L1-negative/gBRCA mutated TN mBC. The Panel critically and comprehensively discussed the most relevant and/or unexpected results and put forward possible interpretations for statements not reaching the consensus threshold.

A network-based, integrative study to identify core biological pathways that drive breast cancer clinical subtypes.

BACKGROUND: The rapid collection of diverse genome-scale data raises the urgent need to integrate and utilise these resources for biological discovery or biomedical applications. For example, diverse transcriptomic and gene copy number variation data are currently collected for various cancers, but relatively few current methods are capable to utilise the emerging information. METHODS: We developed and tested a data-integration method to identify gene networks that drive the biology of breast cancer clinical subtypes. The method simultaneously overlays gene expression and gene copy number data on protein-protein interaction, transcriptional-regulatory and signalling networks by identifying coincident genomic and transcriptional disturbances in local network neighborhoods. RESULTS: We identified distinct driver-networks for each of the three common clinical breast cancer subtypes: oestrogen receptor (ER)+, human epidermal growth factor receptor 2 (HER2)+, and triple receptor-negative breast cancers (TNBC) from patient and cell line data sets. Driver-networks inferred from independent datasets were significantly reproducible. We also confirmed the functional relevance of a subset of randomly selected driver-network members for TNBC in gene knockdown experiments in vitro. We found that TNBC driver-network members genes have increased functional specificity to TNBC cell lines and higher functional sensitivity compared with genes selected by differential expression alone. CONCLUSION: Clinical subtype-specific driver-networks identified through data integration are reproducible and functionally important.

Petrography of construction and demolition waste (CDW) from Abruzzo region (Central Italy).

The density, colour and texture, plus mineral and chemical features of 18 ceramic-like CDW samples from the Abruzzo region (Central Italy) were characterised. The concretes, natural stones, tiles, roof-tiles, bricks and perforated bricks are either aphanitic to porphyric. Concretes and natural stones are grey to white and tend to be > 2.0 g/cm3; the masonries are brown to reddish and close to < 2.0 g/cm3. Concrete and natural stone are rich or even exclusively made up of calcite, with high amounts of CaO (>40 wt%) and LOI (volatiles, CO2 + H2O). The masonries are instead calcite-, CaO- (<25 wt%) and LOI-poor (<8 wt%) but enriched in SiO2 (45 to 70 wt%) stabilised as quartz and/or cristobalite, with significant amount of Al2O3 (12 to 20 wt%). S and Cl contents are similar among concrete, bricks and perforated bricks. The petrography of CDW concretes is similar among geographical areas with abundance of limestones used as aggregates. However, in limestone-poor areas CDW are SiO2- and Al2O3-rich, reflecting the prevalent use of masonry and/or silicate-rich construction materials, implying that each geographical area is characterised by peculiar CDW composition. Therefore, the knowledge of mesoscopic, physical and petrographic aspects has to be known for planning adequate sorting methods, promoting upcycling reusing applications. Some of the studied CDW samples are susceptible to release relative high Cr and As content.

Optimizing treatment management of trastuzumab deruxtecan in clinical practice of breast cancer.

INTRODUCTION: The antibody-drug conjugate trastuzumab deruxtecan (T-DXd) targets human epidermal growth factor receptor 2 (HER2) and has been evaluated in patients with HER2-positive unresectable/metastatic breast cancer in the phase II DESTINY-Breast01 trial (NCT03248492; DS8201-A-U201) and the randomized phase III DESTINY-Breast03 trial (NCT03529110; DS8201-A-U302). Approximately 20 additional studies are ongoing in breast cancer, including HER2-low breast cancer, and other solid tumor types within the DESTINY trial program. T-DXd has demonstrated a generally manageable safety profile, with low-grade hematologic and gastrointestinal adverse events (AEs) among the most common; interstitial lung disease (ILD)/pneumonitis has been observed in patients receiving T-DXd and can be severe. This review discusses the management of common AEs and AEs of special interest in patients with HER2-positive unresectable/metastatic breast cancer, including nausea and vomiting, neutropenia, infusion-related reactions, alopecia, fatigue, ILD/pneumonitis, and left ventricular dysfunction. METHODS: Expert opinions, institutional protocols, and strategies to help optimize AE management and maximize the potential benefits of T-DXd in patients with breast cancer from five oncologists treating patients with T-DXd in North America and Europe are discussed. RESULTS: Prophylaxis for nausea and vomiting and proactive management of ILD/pneumonitis are especially important in treating patients with T-DXd. Management strategies for other T-DXd-related AEs of interest (e.g. neutropenia, infusion-related reactions, alopecia, fatigue, and left ventricular dysfunction) are also discussed. CONCLUSIONS: This review provides context for understanding the usage, monitoring, and management practices of other health care providers and institutions with experience using T-DXd to help with safe and effective management of T-DXd-related AEs, particularly since the duration of T-DXd treatment may be quite long. Proper management of T-DXd-related AEs will allow optimal exposure and benefit from T-DXd and will help avoid premature discontinuation or improper dose reductions.

The occurrence of 2-methylhopanoids in modern bacteria and the geological record.

The 2-methylhopanes (2-MeHops) are molecular fossils of 2-methylbacteriohopanepolyols (2-MeBHPs) and among the oldest biomarkers on Earth. However, these biomarkers' specific sources are currently unexplained, including whether they reflect an expansion of marine cyanobacteria. Here, we study the occurrence of 2-MeBHPs and the genes involved in their synthesis in modern bacteria and explore the occurrence of 2-MeHops in the geological record. We find that the gene responsible for 2-MeBHP synthesis (hpnP) is widespread in cyano- and ⍺-proteobacteria, but absent or very limited in other classes/phyla of bacteria. This result is consistent with the dominance of 2-MeBHP in cyano- and ⍺-proteobacterial cultures. The review of their geological occurrence indicates that 2-MeHops are found from the Paleoproterozoic onwards, although some Precambrian samples might be biased by drilling contamination. During the Phanerozoic, high 2-MeHops' relative abundances (index >15%) are associated with climatic and biogeochemical perturbations such as the Permo/Triassic boundary and the Oceanic Anoxic Events. We analyzed the modern habitat of all hpnP-containing bacteria and find that the only one species coming from an undisputed open marine habitat is an ⍺-proteobacterium acting upon the marine nitrogen cycle. Although organisms can change their habitat in response to environmental stress and evolutionary pressure, we speculate that the high sedimentary 2-MeHops' occurrence observed during the Phanerozoic reflect ⍺-proteobacteria expansion and marine N-cycle perturbations in response to climatic and environmental change.

How I treat HER2-positive early breast cancer: how long adjuvant trastuzumab is needed?

Since its first approval in 2006, 1 year of adjuvant trastuzumab has been the standard of care for early-stage HER2-positive breast cancer. Nevertheless, the optimal duration of adjuvant trastuzumab was uncertain, and the standard 12-month duration has been questioned by a number of different trials. Although most of these studies were formally negative, a patient-level meta-analysis presented at the 2021 European Society for Medical Oncology (ESMO) meeting first showed the non-inferiority of 6-month trastuzumab. Through this review, we sought to take a closer look at the meta-analysis and the included trials to explain why we believe that non-inferiority should be interpreted with caution. Indeed, here we underline how the meta-analysis' results were mainly driven by the PERSEPHONE study, an old trial that tested non-standard chemo-trastuzumab regimens in a relatively low-risk population with doubtful endpoints. In summary, considering all the limitations of this analysis and the increasing use of effective anthracycline-free de-escalation strategies, we are convinced that 1-year trastuzumab should remain the standard of care.

In situ measurements of the physical characteristics of Titan's environment.

On the basis of previous ground-based and fly-by information, we knew that Titan's atmosphere was mainly nitrogen, with some methane, but its temperature and pressure profiles were poorly constrained because of uncertainties in the detailed composition. The extent of atmospheric electricity ('lightning') was also hitherto unknown. Here we report the temperature and density profiles, as determined by the Huygens Atmospheric Structure Instrument (HASI), from an altitude of 1,400 km down to the surface. In the upper part of the atmosphere, the temperature and density were both higher than expected. There is a lower ionospheric layer between 140 km and 40 km, with electrical conductivity peaking near 60 km. We may also have seen the signature of lightning. At the surface, the temperature was 93.65 +/- 0.25 K, and the pressure was 1,467 +/- 1 hPa.

Contributi scientifici in memoria di Antonio Fusco.

Come si leggerà nell'Introduzione della sezione propriamente scientifica del Volume, il presente testo nasce dalla volontà e, soprattutto, dall'esigenza culturale di omaggiare il fu Prof. Antonio Fusco. Un debito scientifico ed umano che trova il suo locus naturale in questa prima parte del testo stesso, cui farà poi seguito la parte propriamente scientifica. In siffatta parentesi dovuta per le ragioni appena menzionate, il lettore, l'amico o l'allievo dell'opera del Prof. Fusco potranno trovare un suo sintetico Curriculum Vitae, correlato da una specifica ed accurata prosa, svolta dal già Magnifico Rettore Carlo Cipolli; il quale, oltre che evidenziare, ricordando, i meriti del collega oramai scomparso, aggiunge alsuo scritto un elemento che sarebbe imprescindibile a non trasformare lo stesso in una mera sequenza di parole: l'amicizia e l'affetto per un amico che, oramai, non c'è più. A fine lettura, evidente risuonerà il fatto che la vita di ognuno, se mossa dalla passione per ciò per cui si è predisposti cognitivamente e psicologicamente, può essere ricca di riconoscimenti, riconoscenze e soddisfazioni che, lungi dal divenire un cuscino di allori su cui adagiarsi, per una mente creativa come quella del Prof. Fusco hanno funto solo da motivazioni ad agire instancabilmente guardando sempre al futuro. Il lavoro di una vita che, materialmente, è sancito da un supporto poco più di cm 25x15: una targa. Una materialità evidente che, con grande commozione e riconoscenza, è stata affissa il 25 ottobre 2019 sull'aula fronte l'Aula Magna del Campus "La Folcara", a testimonianza che quello spirito creativo in continua evoluzione non si ferma; non si arresta neppure con la fine biologica di chi lo ha "posseduto". Rimangono le opere ed il pensiero del Prof. Fusco e restano gli affetti. A tal proposito, il lettore troverà una breve e sentita sezione su Testimonianze; coloro i quali hanno avuto modo, nell'arco della vita accademica ed umana, personale, di Fusco di conoscerlo. Ecco, allora, che i ricordi saranno i veri protagonisti di questa parentesi. Dopo di ciò, prima dei contributi prettamente scientifici dei lavori, tenutisi in occasione del Convegno Internazionale Psicologia, Arte, Letteratura. Antiche e Nuove Tendenze, seguiranno i saluti delle autorità che in quei due giorni si sono succedute a rappresentare non solo l'istituzione affiliata, ma anche la relazione di stima e di affetto che le legava al compianto Professore. Si passerà, infine, al volume tradizionalmente inteso.

Clinical, genetic, and cellular analysis of 49 osteopetrotic patients: implications for diagnosis and treatment.

BACKGROUND: Osteopetrosis, a genetic disease characterised by osteoclast failure, is classified into three forms: infantile malignant autosomal recessive osteopetrosis (ARO), intermediate autosomal recessive osteopetrosis (IRO), and autosomal dominant osteopetrosis (ADO). METHODS: We studied 49 patients, 21 with ARO, one with IRO, and 27 with type II ADO (ADO II). RESULTS: Most ARO patients bore known or novel (one case) ATP6i (TCIRG1) gene mutations. Six ADO II patients had no mutations in ClCN7, the only so far recognised gene implicated, suggesting involvement of yet unknown genes. Identical ClCN7 mutations produced differing phenotypes with variable degrees of severity. In ADO II, serum tartrate resistant acid phosphatase was always elevated. Bone alkaline phosphatase (BALP) was generally low, but osteocalcin was high, suggesting perturbed osteoblast differentiation or function. In contrast, BALP was high in ARO patients. Elevated osteoclast surface/bone surface was noted in biopsies from most ARO patients. Cases with high osteoclasts also showed increased osteoblast surface/bone surface. ARO osteoclasts were morphologically normal, with unaltered formation rates, intracellular pH handling, and response to acidification. Their resorption activity was greatly reduced, but not abolished. In control osteoclasts, all resorption activity was abolished by combined inhibition of proton pumping and sodium/proton antiport. CONCLUSIONS: These findings provide a rationale for novel therapies targeting pH handling mechanisms in osteoclasts and their microenvironment.

[Usefulness of a questionnaire and RAST in screening of health care workers allergic to latex]. / Utilità del questionario e del RAST nello screening di operatori sanitari allergici al lattice.

BACKGROUND: The prevalence of latex mediated IgE allergy in health care workers varies, according to the various studies, from 0.5% to 16. 7%. The onset of latex allergy involves aspects concerning the worker's health, the need for job transfer and possible retraining. In any case, the use of latex gloves in health care environments cannot be discarded, since they offer more efficacious protection from biological agents, compared to gloves of different materials. OBJECTIVES: Our objectives were to verify the prevalence of latex allergy in a sample of 515 health care workers and evaluate the usefulness of RAST and a questionnaire especially organized to identify potentially allergic subjects, at the same time limiting the number of false positive and false negative results. METHODS: 515 health care workers of the ASUR Zone7-Ancona local health unit accepted to answer to a questionnaire and to undergo a RAST testfor latex. Those with positive responses to the questionnaire or to RAST were later invited to undergo further allergological tests (prick and prick by prick). The questionnaire was revised according to the results obtained, thus increasing its positive predictiveness. RESULTS: Prevalence of latex allergy in our sample was 1, 7%, positive predictiveness of RAST was rather low (31.3%), but increased considerably if combined with the modified questionnaire (62.5%). The Prick by Prick test gave more specific results than the Prick test. CONCLUSIONS: The proposed questionnaire can reduce the number of false positive workers needing to undergo further allergological tests and may be usefully applied in the screening of latex mediated IgE allergy in health care workers.

Geochemistry of the Adige River water from the Eastern Alps to the Adriatic Sea (Italy): evidences for distinct hydrological components and water-rock interactions.

The Adige River flows from the Eastern Alps to the Adriatic Sea and the understanding of its fluvial dynamics can be improved by geochemical and O-H isotopic investigation. The most negative isotopic compositions are recorded close to the source (δ(18)O between -14.1 and -13.8 ‰, δD between -100.3 and -97.0 ‰), and δD and δ(18)O values generally increase downstream through the upper part (UP, the mountainous sector), stabilizing along the lower part (LP, the alluvial plain) of the river with δ(18)O between -12.4 and -11.8 ‰, δD between -86.9 and -83.7 ‰. The isotopic variations along the stream path (δ(18)O-δD vs distance from the source) depict subparallel distributions for all the investigated periods, with less negative values recorded in winter. Total dissolved solids (TDS) concentration shows the lowest value (<100 mg/l) at the river source, jumping to 310 mg/l at the Rio Ram inflow, then decreasing down to the Isarco River confluence; from here, we observed an increase toward the river mouth, with different values in the distinct sampling periods. The lowest values (140-170 mg/l) were recorded during high discharge in spring, whereas higher TDS values (up to 250 mg/l) were recorded during winter low flow conditions. Extreme TDS values were observed in the estuarine samples (up to 450 mg/l), as result of mixing with seawater. The results allow for the identification of distinct water end-members: glacio-nival component(s) characterized by the most negative isotopic composition and extremely low TDS, a rainfall component characterized by intermediate isotopic and elemental composition and groundwater characterized by the less negative isotopic composition and comparatively higher TDS. An additional component is represented by seawater, which is recorded at the lowest reach of the river during drought periods. These contributions variously mix along the stream path in the distinct hydrological periods, and the presented data are a snapshot of the current hydroclimatic conditions. Future investigations will evaluate possible hydrological variations related to meteo-climatic changes. Monitoring is fundamental for future water management to overcome the vanishing of a significant water end-member of the basin, i.e., the glacio-nival reservoir that is severely affected by the ongoing climatic changes.

Adenylate cyclase activity in cyanobacteria: activation by Ca(2+)-calmodulin and a calmodulin-like activity.

An adenylate cyclase activity was partially characterized in the cyanobacterium Anabaena sp. The enzyme activity is found in soluble cell fractions and shows an apparent molecular weight of about 183,400. This adenylate cyclase is activated by Ca2+ and bovine brain or spinach calmodulin and it is inhibited by EGTA and some phenothiazine derivatives. Furthermore, Anabaena sp. extracts contain a calmodulin-like activity which stimulates bovine brain cyclic AMP phosphodiesterase and the Anabaena adenylate cyclase. EGTA and phenothiazine derivatives block the cyanobacterial modulator effect.