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COVID-19 syndrome is characterized by acute lung injury, hypoxemic respiratory failure, and high mortality. Alveolar type 2 (AT2) cells are essential for gas exchange, repair, and regeneration of distal lung epithelium. We have shown that the causative agent, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), and other members of the β-coronavirus genus induce an endoplasmic reticulum (ER) stress response in vitro; however, the consequences for host AT2 cell function in vivo are less understood. To study this, two murine models of coronavirus infection were used-mouse hepatitis virus-1 (MHV-1) in A/J mice and a mouse-adapted SARS-CoV-2 strain. MHV-1-infected mice exhibited dose-dependent weight loss with histological evidence of distal lung injury accompanied by elevated bronchoalveolar lavage fluid (BALF) cell counts and total protein. AT2 cells showed evidence of both viral infection and increased BIP/GRP78 expression, consistent with activation of the unfolded protein response (UPR). The AT2 UPR included increased inositol-requiring enzyme 1α (IRE1α) signaling and a biphasic response in PKR-like ER kinase (PERK) signaling accompanied by marked reductions in AT2 and BALF surfactant protein (SP-B and SP-C) content, increases in surfactant surface tension, and emergence of a reprogrammed epithelial cell population ( Krt8 + and Cldn4 + ). The loss of a homeostatic AT2 cell state was attenuated by treatment with the IRE1α inhibitor OPK-711. As a proof-of-concept, C57BL6 mice infected with mouse-adapted SARS-CoV-2 demonstrated similar lung injury and evidence of disrupted surfactant homeostasis. We conclude that lung injury from β-coronavirus infection results from an aberrant host response, activating multiple AT2 UPR stress pathways, altering surfactant metabolism/function, and changing AT2 cell state, offering a mechanistic link between SARS-CoV-2 infection, AT2 cell biology, and acute respiratory failure. NEW & NOTEWORTHY COVID-19 syndrome is characterized by hypoxemic respiratory failure and high mortality. In this report, we use two murine models to show that β-coronavirus infection produces acute lung injury, which results from an aberrant host response, activating multiple epithelial endoplasmic reticular stress pathways, disrupting pulmonary surfactant metabolism and function, and forcing emergence of an aberrant epithelial transition state. Our results offer a mechanistic link between SARS-CoV-2 infection, AT2 cell biology, and respiratory failure.

This work reports on the properties of heterojunctions consisting of n -type Ga 2 O 3 layers, deposited using ultrasonic spray pyrolysis at high temperature from water-based solution, combined with p -type NiO and Cu 2 O counterparts, deposited by radio frequency and reactive, direct-current magnetron sputtering, respectively. After a comprehensive investigation of the properties of the single layers, the fabricated junctions on indium tin oxide (ITO)-coated glass showed high rectification, with an open circuit voltage of 940 mV for Ga 2 O 3 /Cu 2 O and 220 mV for Ga 2 O 3 /NiO under simulated solar illumination. This demonstrates in praxis the favorable band alignment between the sprayed Ga 2 O 3 and Cu 2 O, with small conduction band offset, and the large offsets anticipated for both energy bands in the case of Ga 2 O 3 /NiO. Large differences in the ideality factors between the two types of heterojunctions were observed, suggestive of distinctive properties of the heterointerface. Further, it is shown that the interface between the high-temperature-deposited Ga 2 O 3 and the ITO contact does not impede electron transport, opening new possibilities for the design of solar cell and optoelectronic device architectures.

Idiopathic pulmonary fibrosis (IPF) is a chronic progressive fibrotic interstitial lung disease. A barrier to developing more effective therapies for IPF is the dearth of preclinical models that recapitulate the early pathobiology of this disease. Intratracheal bleomycin, the conventional preclinical murine model of IPF, fails to reproduce the intrinsic dysfunction to the alveolar epithelial type 2 cell (AEC2) that is believed to be a proximal event in the pathogenesis of IPF. Murine fibrosis models based on SFTPC (Surfactant Protein C gene) mutations identified in patients with interstitial lung disease cause activation of the AEC2 unfolded protein response and endoplasmic reticulum stress-an AEC2 dysfunction phenotype observed in IPF. Although these models achieve spontaneous fibrosis, they do so with precedent lung injury and thus are challenged to phenocopy the general clinical course of patients with IPF-gradual progressive fibrosis and loss of lung function. Here, we report a refinement of a murine Sftpc mutation model to recapitulate the clinical course, physiological impairment, parenchymal cellular composition, and biomarkers associated with IPF. This platform provides the field with an innovative model to understand IPF pathogenesis and index preclinical therapeutic candidates.

Farming in Europe has been the scene of several important socio-economic and environmental developments and crises throughout the last century. Therefore, an understanding of the historical driving forces of farm change helps identifying potentials for navigating future pathways of agricultural development. However, long-term driving forces have so far been studied, e.g. in anecdotal local case studies or in systematic literature reviews, which often lack context dependency. In this study, we bridged local and continental scales by conducting 123 oral history interviews (OHIs) with elderly farmers across 13 study sites in 10 European countries. We applied a driving forces framework to systematically analyse the OHIs. We find that the most prevalent driving forces were the introduction of new technologies, developments in agricultural markets that pushed farmers for farm size enlargement and technological optimisation, agricultural policies, but also cultural aspects such as cooperation and intergenerational arrangements. However, we find considerable heterogeneity in the specific influence of individual driving forces across the study sites, implying that generic assumptions about the dynamics and impacts of European agricultural change drivers hold limited explanatory power on the local scale. Our results suggest that site-specific factors and their historical development will need to be considered when addressing the future of agriculture in Europe in a scientific or policy context., Supplementary Information: The online version contains supplementary material available at 10.1007/s10113-023-02150-y., (© The Author(s) 2023.)

This work examined the short and long-term effects of different free ammonia (FA) and free nitrous acid (FNA) levels on (i) acclimatized biomass treating sludge reject water via nitrite in a sequencing batch reactor (SBR) and (ii) non-aclimatized biomass treating municipal wastewater via nitrate in the activated sludge process. In the acclimatized biomass, the threshold for the transition from nitrification to nitritation was the FA increase to 10-20 mgNH 3 -N/L while the SBR unit showed no inhibition on the ammonia uptake rate (AUR) at FA levels up to 65 mgNH 3 -N/L. Short-term exposure of the acclimatized biomass on FNA showed that AUR inhibition could be more than 50 % for FNA concentration >10 μgHNO 2 -N/L. The FNA inhibition results were simulated using non-competitive inhibition kinetics that showed that the inhibition constant corresponding to the FNA concentration that inhibits the process by 50 % (i.e. K iFNA ) was much higher in the acclimatized biomass., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Landscape products link to low-input practices and traditional ecological knowledge, and have multiple functions supporting human well-being and sustainability. Here we explore seven landscape products worldwide to identify these multiple functions in the context of food commodification and landscape sustainability. We show that a landscape products lens can improve food systems by fostering sustainability strategies and standards that are place-sensitive, and as such can mitigate conflicts related to food production, social justice and the environment. Co-management strategies and information policies, such as certification, labelling, product information and raising of awareness could accelerate, incentivize and catalyse actions to support landscape products in the context of sustainability strategies., (© 2022. Springer Nature Limited.)

The management of agroecosystems affects biodiversity at all levels from genetic to food-web complexity. Low-input farming systems support higher levels of genetic, species and habitat diversity than high-input, industrial ones. In Greece, as in other Mediterranean countries, the role of traditional farming practices has been underlined in studies concerning conservation in agricultural landscapes. With this study, we aim to provide evidence for the potential of semi-extensive farming for biodiversity conservation at landscape-scale, focusing on Lemnos, a medium-sized island in the North Aegean. Evidence was gathered by species- and community-level local-scale surveys on various trophic levels (vascular plants, arthropods, birds). The surveys took place in 2018 and 2019 in 25 sampling areas comprising 106 plots of 100 m 2 (vascular plants, arthropods) and 57 points where bird species were recorded. The plots were classified into three landscape types: mosaic agriculture, mixed rangelands and uniform rangelands. The relevés of Lemnos farmlands were assigned to plant communities of 18 phytosociological alliances, grouped into 12 classes. The most abundant arthropods were Coleoptera, Chilopoda, and Hymenoptera, followed by Opiliones and Isopoda, while 133 different bird species were recorded in total, including the recording for the first time on the island of five species. Farming on Lemnos is rather extensive compared to most agricultural landscapes of Europe. Our approach has demonstrated that, given the geographic characteristics of the area, the measured data reveal very high biodiversity. Our explorative findings suggest that moderate seasonal grazing, the mixed habitat mosaic with ecotones, fallow and stubble fields at the landscape scale, and the small size of fields, the kinds of crop, and farm-scale crop diversification, like mixed cultivation and crop rotation, are key practices supporting this diversity. These explorative findings are considered as a first step providing the baseline for future assessments. A wider effort, for systematic evaluation of the impacts of farming practices to biodiversity, is required, as part of a subsidized agri-environmental scheme and/or through a market-oriented product certification system for the area., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

A flexible transparent heater is presented, based on an all-sprayed composite architecture of indium-doped zinc oxide (IZO) layers that sandwich a network of silver nanowires, on a polyimide-foil substrate. This architecture could be materialized through the development of a low-temperature (240 °C) spray-pyrolysis process for the IZO layers, which is compatible with the thermal stability of the transparent polyimide substrate and allows for the formation of compact and transparent layers, without precipitates. The IZO layers entirely embed the silver nanowires, offering protection against environmental degradation and decreasing the junction resistance of the nanowire network. The resulting transparent heaters have a high mean transmittance of 0.76 (including the substrate) and sheet resistance of 7.5 Ω/sq. A steady-state temperature of ~130 °C is achieved at an applied bias of 3.5 V, with fast heater response times, with a time constant of ~4 s The heater is mechanically stable, reaching or surpassing 100 °C (at 3.5 V), under tensile, respectively, compressive-bending stress. This work shows that high-performance transparent heaters can be fabricated using all-sprayed oxide/silver-nanowire composite coatings, that are compatible with large-scale and low-cost production.

It has been shown that the COVID-19 pandemic affected some agricultural systems more than others, and even within geographic regions, not all farms were affected to the same extent. To build resilience of agricultural systems to future shocks, it is key to understand which farms were affected and why. In this study, we examined farmers' perceived robustness to COVID-19, a key resilience capacity. We conducted standardized farmer interviews ( n = 257) in 15 case study areas across Europe, covering a large range of socio-ecological contexts and farm types. Interviews targeted perceived livelihood impacts of the COVID-19 pandemic on productivity, sales, price, labor availability, and supply chains in 2020, as well as farm(er) characteristics and farm management. Our study corroborates earlier evidence that most farms were not or only slightly affected by the first wave(s) of the pandemic in 2020, and that impacts varied widely by study region. However, a significant minority of farmers across Europe reported that the pandemic was "the worst crisis in a lifetime" (3%) or "the worst crisis in a decade" (7%). Statistical analysis showed that more specialized and intensive farms were more likely to have perceived negative impacts. From a societal perspective, this suggests that highly specialized, intensive farms face higher vulnerability to shocks that affect regional to global supply chains. Supporting farmers in the diversification of their production systems while decreasing dependence on service suppliers and supply chain actors may increase their robustness to future disruptions., Supplementary Information: The online version contains supplementary material available at 10.1007/s13593-022-00820-5., Competing Interests: Conflict of interestThe authors declare no competing interests., (© The Author(s) 2022.)

The broad application of flexible optoelectronic devices is still hampered by the lack of an ITO-free and highly flexible transparent electrode. Dielectric/metal/dielectric (DMD) transparent electrodes are promising candidates to replace ITO, especially in flexible devices due to their mechanical stability to bending, high optical transmittance and low sheet resistance (<6 Ω sq -1 ). This paper reports on organic light emitting diodes (OLEDs) employing a DMD electrode, specifically TiO x /Ag/Al:ZnO (doped with 2 wt% Al 2 O 3 ) fabricated by sputter deposition, together with a solution-processed organic polymeric emitting layer. The electrodes were sputtered without substrate heating on rigid glass and flexible polyethylene terephthalate (PET). The results showed that the OLED devices on the DMD electrodes outperform the OLEDs on commercial ITO substrates in terms of maximum luminance as well as current efficacy. Specifically, DMD-based devices achieve up to 30% higher current efficacy on glass and up to 260% higher efficacy on PET, as compared to the ITO-based reference devices. Maximum luminance reaches up to 100 000 cd m -2 for the DMD-based OLEDs on glass and 43 000 cd m -2 for those on PET. This performance is due to the low sheet resistance of the electrodes combined with efficient light outcoupling and shows the potential of DMDs to replace ITO in optoelectronic devices. This outstanding type of optoelectronic device paves the way for the future high throughput production of flexible display and photovoltaic devices., Competing Interests: The authors declare no competing financial interest., (This journal is © The Royal Society of Chemistry.)

The present study investigates processing routes to obtain highly conductive and transparent electrodes of silver nanowires (AgNWs) on flexible polyethylene terephthalate (PET) substrate. The AgNWs are embedded into a UV-curable polymer to reduce the electrode roughness and enhance its stability. For the purpose of device integration, the AgNWs must partially protrude from the polymer, which demands that their embedding is followed by a transfer step from a host substrate to the final substrate. Since the AgNWs require some sort of curing (thermal or plasma) to reduce the electrode sheet resistance, a thermally stable host substrate is generally used. This study shows that both thermally stable polyimide, as well as temperature-sensitive PET can be used as flexible host substrates, combined with a gentle, AgNW plasma curing. This is possible by adjusting the fabrication sequence to accommodate the plasma curing step, depending on the host substrate. As a result, embedded AgNW electrodes, transferred from polyimide-to-PET and from PET-to-PET are obtained, with optical transmittance of ∼80% (including the substrate) and sheet resistance of ∼13 Ω/sq., similar to electrodes transferred from glass-to-glass substrates. The embedded AgNW electrodes on PET show superior performance in bending tests, as compared to indium-tin-oxide electrodes. The introduced approach, involving low-cost flexible substrates, AgNW spray-coating and plasma curing, is compatible with high-throughput, roll-to-roll processing.

In this study, ultrathin silver plasmonic nanostructures are fabricated by sputter deposition on substrates patterned by nanoimprint lithography, without additional lift-off processes. Detailed investigation of silver growth on different substrates results in a structured, defect-free silver film with thickness down to 6 nm, deposited on a thin layer of doped zinc oxide. Variation of the aspect ratio of the nanostructure reduces grain formation at the flanks, allowing for well-separated disk and hole arrays, even though conventional magnetron sputtering is less directional than evaporation. The resulting disk-hole array features high average transmittance in the visible range of 71% and a strong plasmonic dipole resonance in the near-infrared region. It is shown that the ultrathin Ag film exhibits even lower optical losses in the NIR range compared to known bulk optical properties. The presented FDTD simulations agree well with experimental spectra and show that for defect-free, ultrathin Ag nanostructures, bulk optical properties of Ag are sufficient for a reliable simulation-based design., Competing Interests: There are no conflicts to declare., (This journal is © The Royal Society of Chemistry.)

Nanostructured surfaces and nanoparticles are already widely employed in many different fields of research, and there is an ever-growing demand for reliable, reproducible and scalable nanofabrication methods. This is especially valid for multifunctional nanomaterials with physical properties that are tailored for specific applications. Here, we report on the fabrication of two types of nanomaterials. Specifically, we present surfaces comprising a highly uniform array of elliptical pillars as well as nanoparticles with the shape of nanopockets, possessing nano-cavities. The structures are fabricated by nanoimprint lithography, physical and wet-chemical etching and sputter deposition of thin films of various materials to achieve a multifunctional nanomaterial with defined optical and magnetic properties. We show that the nanopockets can be transferred to solution, yielding a nanoparticle dispersion. All fabrication steps are carefully characterized by microscopic and optical methods. Additionally, we show optical simulation results that are in good agreement with the experimentally obtained data. Thus, this versatile method allows to fabricate nanomaterials with specific tailor-made physical properties that can be designed by modelling prior to the actual fabrication process. Finally, we discuss possible application areas of these nanomaterials, which range from biology and medicine to electronics, photovoltaics and photocatalysis.

A nanostructured transparent electrode with high average visible transmittance of 76%, low sheet resistance of 7.0 Ω/sq and steep transmittance drop in the near-infrared (NIR) range is investigated by simulations and experiments. The electrode is composed of a nanostructured substrate, on which a trilayer, consisting of an ultrathin 14 nm thick silver film embedded between thin films of TiO 2 and Al-doped ZnO, is deposited. Directional silver deposition results in the formation of a disk-hole array without additional lift-off or etching steps. While the trilayer approach enables increased visible transmittance, the transmittance in the NIR regime is decreased by a broadband plasmonic dipole excitation in the disk-hole array. Moreover, a rich mode spectrum of weaker multipole surface plasmon excitations is observed in the nanodisk- and nanohole array. The presented electrode holds great potential for applications in optoelectronic devices, solar control coatings and solar cells.

In this contribution, we present the synthesis and characterization of the mixed-anion halogenobismuthate(III) (CH 3 NH 3 ) 6 BiI 5.22 Cl 3.78 (MBIC) as an alternative lead-free perovskite-type semiconductor, and discuss its optical, electronic, and photovoltaic properties in comparison to the methylammonium bismuth iodide (CH 3 NH 3 ) 3 Bi 2 I 9 (MBI) compound. The exchange of iodide with chloride during synthesis leads to the formation of an orthorhombic A 6 BX 9 -type crystal structure ( Cmma, No. 67) with isolated BiX 6 octahedra and methylammonium chloride interlayers. The experimentally found optical indirect band gap of 2.25 eV is in good agreement with the calculated value of 2.50 eV derived from DFT simulations. The valence band maximum and the conduction band minimum were determined to be at -6.2 eV and -4.0 eV vs vacuum. Similar to MBI, thin films of MBIC are composed of microcrystalline platelets. Time-resolved photoluminescence measurements show electron transfer of MBIC to mesoporous TiO 2 . The photovoltaic behavior of both compounds is compared in solar cells with the following device architecture: glass/ITO/compact TiO 2 /mesoporous TiO 2 /MBIC or MBI/spiro-OMeTAD/Au. Despite the zero-dimensional structure of MBIC, a maximum power conversion efficiency of 0.18% and a high fill factor of almost 60% were obtained with this material as absorber layer. When stored under inert conditions, these solar cells show an excellent long-term stability over the investigated period of more than 700 days.

Indium tin oxide (ITO) thin films were sputter-deposited at ambient temperature on a glass-like substrate that was periodically nanostructured by UV nanoimprint lithography. Cross gratings of the corrugated and conformal ITO, with different periods and modulation depths, were tailored to exhibit light trapping or antireflection properties at specific spectral windows by combined optical simulations and experiments. For dense gratings, the light transmission in the 450-850 nm range was enhanced by 8% (absolute) compared to flat ITO films, which is one of the largest performance improvements reported in the literature for nanostructured transparent electrodes. Increasing the grating period shifts the threshold for diffraction coupling to waveguide modes in the visible and near infrared part of the spectrum, resulting in broad light trapping behaviour at wavelengths below this threshold. This work demonstrates a simple processing route at ambient temperature for the fabrication of high-performance transparent electrodes in order to fulfil different device requirements.

Transparent electrodes based on an ultrathin Cu layer, embedded between two dielectrics, are optimized by simulations and experiments. Different dielectrics are screened in transfer matrix simulations for maximizing the broad-band transmittance. Based on this, sputtered electrodes were developed with the Cu embedded between TiO X -coated glass or PET substrate and an Al-doped ZnO (AZO) top layer. It is found that, for ultrathin Cu layers, increased sputter power fosters island coalescence, leading to superior optical and electrical performance compared to previously reported Cu-based electrodes. Simulations showed that the electrode design optimized with air as ambient medium has to be adapted in the case of electrode implementation in a hybrid perovskite solar cell of inverted architecture.

The methods employed for the detection of circulating bladder cancer cells (CBCs) and their use as a molecular staging tool in clinical settings are thoroughly reviewed. CBC isolation and enrichment methods are discussed according to their advantages and pitfalls along with the clinical data of PCR-based techniques used for CBC detection. In addition, we review the specificity of molecular markers that have been proposed so far for CBC identification, and we comment on the controversial clinical data, proposing laboratory approaches which may improve the clinical significance of CBC detection in bladder cancer.

Background: The clinical relevance of positive molecular staging as defined by reverse transcriptase-polymerase chain reaction (RT-PCR) detections of both prostate-specific antigen (PSA) and prostate-specific membrane antigen (PSMA) transcripts in the peripheral blood (PB) of patients with prostate cancer is still debatable., Methods: We analyzed the biochemical failure-free survival (bFFS) of prostate cancer patients with positive molecular staging who underwent immediate curative therapy (Group I, n=39) compared to prostate cancer patients who did convert their positive molecular staging by the administration of combined androgen blockade (CAB) for 12 months prior to curative treatment (Group II, n=15)., Results: The median bFFS for Group I was 9 months (95% CI 5-13 months) and was significantly lower compared to Group II (>36 months, p<0.001). In Group I, the median time for PSA values of >2.0 ng/mL was 18 months (95% CI 12-21 months, range 12-36 months). Notably, only one patient from Group II reached PSA values>2.0 ng/mL at 36 months post-curative treatment., Conclusions: In patients with clinically localized prostate cancer and positive RT-PCR detection of PSA and PSMA transcripts in PB, CAB can convert positive molecular staging status to negative and by doing so it modifies the post-curative therapy bFFS of patients with clinically localized prostate cancer.

Background: As previously shown, the combination of standard androgen ablation therapy with somatostatin analog and dexamethasone in metastatic androgen ablation-refractory (stage D3) prostate cancer (PrCa) patients has a favorable profile of side-effects, durable objective antitumor activity (up to 60% partial response rate) and palliative effects. Bisphosphonates interfere with bone remodeling at the sites of PrCa bone metastases and have been postulated to have indirect and/or direct anti-PrCa activity., Materials and Methods: A randomized controlled clinical trial was conducted to compare a combination of somatostatin analog (octreotide 20 mg i.m. every 28 days) and oral dexamethasone (4 mg daily for 1 month, gradually reduced to 1 mg daily by the fourth month, with a 1 mg daily maintenance dose thereafter) plus zoledronate (4 mg i.v. every 4 weeks) vs. zoledronate only. All patients in both arms remained in basic androgen blockade throughout the study., Results: Thirty-eight stage D3 patients (mean age 72.8 +/- 6.8 years) were randomized to either treatment arm of the study. The trial was stopped after a pre-specified interim analysis met the criteria for early closure, i.e. significant difference in outcomes between the two treatment arms. Partial responses (PR, > or =50% PSA decline) were observed in 13 out of 20 patients with combination therapy vs. none with zoledronate. The combination therapy arm had significantly better outcome with respect to median progression-free survival (7.0 vs. 1.0 months, p < 0.0001), median overall survival (OS) (12.0 vs. 9.0 months, p = 0.0027), median PrCa-specific OS (defined as time from onset of therapy until PrCa-related death) (16 vs. 9.0 months, p = 0.0005) and median duration of bone pain improvement (>14 vs. 4 months p = 0.00001 by log-rank tests)., Conclusion: For androgen ablation-refractory metastatic PrCa patients under androgen ablation, the combination of dexamethasone, somatostatin analog and zoledronate offered superior objective and palliative clinical responses than zoledronate alone.

The development of resistance to anticancer therapies is a major hurdle in preventing long-lasting clinical responses to conventional therapies in hormone-refractory prostate cancer. Herein, the molecular evidence documenting that bone metastasis microenvironment survival factors (mainly the paracrine growth hormone-independent, urokinase-type plasminogen activator-mediated increase of IGF-1 and the endocrine production of growth hormone-dependent IGF-1, mainly liver-derived IGF-1 production) produce an epigenetic form of prostate cancer cells that are resistant to proapoptotic therapies is reviewed. Consequently, the authors present the conceptual framework of a novel antibone microenvironment survival factor, mainly an anti-IGF-1 hormonal manipulation for androgen ablation refractory prostate cancer (a combination of conventional androgen ablation therapy [luteinising hormone-releasing hormone agonist-A or orchiectomy]) with dexamethasone plus somatostatin analogue, which yielded durable objective responses and major improvement of bone pain and performance status in stage D3 prostate cancer patients.

Purpose: Androgen ablation-refractory prostate cancer patients (stage D3) develop painful bone metastases and limited responsiveness to conventional therapies, hence the lack of universally accepted "gold standard" treatment for this poor prognosis clinical setting. We tested the safety and efficacy in stage D3 patients of the combination hormonal therapy, which combines administration of somatostatin analog and dexamethasone with standard androgen ablation monotherapy (luteinizing-hormone releasing-hormone analog or orchiectomy)., Experimental Design: Thirty eight patients with stage D3 prostate cancer (mean age 71.8 +/- 5.9 years) continued receiving androgen ablation therapy in combination with oral dexamethasone (4 mg daily for the 1st month of treatment, tapered down to 1 mg daily by the 4th month, with 1 mg daily maintenance dose thereafter) and somatostatin analog (20 mg octreotide i.m. injections every 28 days)., Results: Twenty-three of 38 patients (60.5%) receiving this combination regimen had partial responses [PR, >/=50% prostate-specific antigen (PSA) decline], 9 (21.1%) had stable disease, and 7 (18.4%) had progressive disease. In 47.7% (18 of 38) of patients, their serum PSA levels decreased with treatment but did not return to their respective baselines until the end of follow-up (or death from non-prostate cancer-related causes). The median time-to-return to baseline PSA was 12 months (95% CI, 7-17 months), median progression-free survival was 7 months (95% CI, 4.5-9.5 months), median overall survival was 14 months (95% CI, 10.7-17.4 months), and median prostate cancer-specific overall survival (defined as time from onset of combination therapy until prostate cancer-related death) was 16.0 months (95% CI, 11.9-20.1 months). All patients reported significant and durable improvement of bone pain and performance status (for a median duration of 14 months; 95% CI, 9-19 months), without major treatment-related side effects. We observed a statistically significant (P < 0.01) reduction in serum insulin-like growth factor-1 levels at response to the combination therapy. T levels remained suppressed within castration levels at baseline and throughout therapy, including relapse., Conclusion: The combination therapy of dexamethasone plus somatostatin analog and standard androgen ablation manipulation produces objective clinical responses and symptomatic improvement in androgen ablation-refractory refractory prostate cancer patients.

The local microenvironment at the sites of cancer metastases protects tumour cells from anticancer drug-induced apoptosis via mechanisms, such as soluble growth factors and cytokines. The concept of antisurvival factor (ASF) therapy as a component of anticancer treatments aims at neutralising the protective effect conferred upon cancer cells by the survival factor(s) derived by the local microenvironment, in order to enhance the sensitivity and/or reverse the resistance of tumour cells to other anticancer therapeutic strategies. Herein, we review the translation of this concept from ex vivo studies to clinical applications in the setting of prostate cancer refractory to androgen ablation (stage D3). At this stage, which predominantly involves bone metastases, insulin-like growth factor 1 (IGF-1) production (either growth hormone (GH)-dependent or GH-independent) can protect tumour cells from apoptosis, despite the significant suppression of androgens. The application of the ASF therapeutic concept involves the combination of dexamethasone (which suppresses GH-independent IGF-1) and somatostatin analogue (which suppresses endocrine, GH-dependent IGF-1) with the pro-apoptotic effect of the testicular androgen suppression by sustained use of LHRH analogues. In stage D3, patients who had failed anti-androgen withdrawal, chemotherapy and also had several other adverse prognostic features, the ASF-based combination achieved durable objective responses and major symptomatic improvement, paving the way for future applications of this approach. The ASF-based combination therapy illustrates a novel paradigm in cancer treatment: anti-tumour treatment strategies may not only aim at directly inducing cancer cell apoptosis, but can also target the tumour microenvironment and neutralise the protection it confers on metastatic cancer cells. The favourable toxicity profile of this therapeutic approach calls for its testing in a randomised controlled setting in metastatic prostate cancer and, conceivably, in other IGF-1-responsive malignancies.

We evaluated whether the combination of triptorelin, a LHRH analog (LHRH-A), with dexamethasone and lanreotide, a somatostatin analog, can produce objective clinical responses in metastatic androgen ablation-refractory prostate cancer (stage D3) patients who have relapsed, after combined androgen blockade (LHRH-A plus antiandrogen) and antiandrogen withdrawal. Eleven stage D3 patients with diffuse bony metastases, who had progressed despite initial responses (lasting <12 months) to combined androgen blockade therapy and subsequently failed antiandrogen withdrawal, received oral dexamethasone (4 mg daily for the first month, tapered down to 2 mg after the first month and 1 mg after the second month, and continued on 1 mg thereafter) and lanreotide (30 mg im every 14 d) in combination with triptorelin (3.75 mg im every 28 d). Serum prostate-specific antigen, alkaline phosphatase, performance status, and bone pain were assessed monthly during therapy. Fasting blood glucose was measured biweekly, and serum IGF-I, T, and dehydroepiandrosterone sulfate levels were assessed at baseline, at response to the combination therapy, and at relapse from it. Ten of 11 stage D3 patients [90.9% of patients; 95% confidence interval (CI), 58.7-99.8%] had durable objective clinical responses (including > or = 50% prostate-specific antigen decline in 8 patients, 72.7%; 95% CI, 39-94%). All patients reported significant and durable improvement of bone pain (for a median duration of 13 months; 95% CI, 12-14 months; range, 6-22 months) and performance status (median duration, 19 months; 95% CI, 13-25 months; range, 7-22 months) without major treatment-related side effects. The median progression-free survival was 7 months (95% CI, 4-10 months; range, 3-17 months), and the median overall survival was 18 months (95% CI, 16-20 months; range, 7-22 months). Five of six total deaths occurred secondary to disease progression. We observed a statistically significant (P = 0.018) reduction in serum IGF-I levels at response to the combination therapy (60% reduction of baseline IGF-I levels). Dehydroepiandrosterone sulfate levels, although already significantly suppressed at baseline, had an additional significant reduction (P < 0.02) at response to therapy. T levels remained suppressed within castration levels (<3 nmol/liter, at baseline and throughout therapy, including relapse). The combination therapy of LHRH-A with dexamethasone plus somatostatin analog produces objective clinical responses and symptomatic improvement in androgen ablation (LHRH-A) refractory prostate cancer patients.

Background: Nested reverse-transcriptase polymerase chain reaction (nested rt-PCR) for the detection of mRNA of prostate specific antigen (PSA) and prostate specific membrane antigen (PSMA) in peripheral blood samples (PB) and bone marrow biopsies (BM) can assess the extraprostatic growth of prostate cells., Materials and Methods: Nested rt-PCR for PSA and PSMA at PB and BM was performed (a) at diagnosis, (b) after 6 months from the initiation of combined androgen blockade [(CAB); triptorelin 3.75 mg, i.m., q28 days plus flutamide 250 mg, per os, tid] and, (c) at progression to androgen refractory stage in 28 patients with newly-diagnosed stage D2 prostate cancer., Results: At diagnosis, all patients were found to be rt-PCR positive for PSA and PSMA at BM while 7 (25%) were rt-PCR negative for PSA and PSMA at PB. Nine out of 21 patients with rt-PCR-positive status have converted to rt-PCR-negative status at PB during CAB while they remained rt-PCR-positive at BM. The rt-PCR-negative status at PB during CAB was associated with progression-free survival >12 months (p=0.029). At progression to androgen refractory stage all but 2 patients were rt-PCR-positive at PB for PSA and PSMA, among them 3 who were rt-PCR-negative at diagnosis., Conclusion: Our data suggest that conversion to rt-PCR-negative status at PB for PSA and PSMA during objective clinical response to CAB is associated with long progression-free survival in stage D2 disease.

Local transport properties of Al2O3 tunnel barriers have been investigated at a nanometric spatial scale with an unconventional near field microscope. Using the tunneling effect, which is extremely sensitive to fluctuations of the barrier parameters (less than 1 to 2 A), a unique method is introduced to investigate the tunnel barrier quality. This technique provides atomic scale information on the barrier characteristics which cannot be obtained by conventional surface analysis techniques since they are all subject to averaging over surface and depth.

The importance of insulin-like growth factor 1 (IGF-1) in human serum for the early diagnosis of prostate cancer is controversial. The IGF-1/PSA ratio may improve the performance of prostate specific antigen (PSA) as a prostate cancer marker. IGF-1, along with PSA and free PSA concentration, was measured in the serum of 34 patients with prostate cancer and in 131 patients with benign prostatic hyperplasia (BPH). Although IGF-1 concentration did not significantly differ between the groups, PSA/IGF-1 ratio could clearly distinguish the two groups. In patients with cancer but not in patients with BPH, IGF-1 concentration correlated with PSA and free PSA. The values of PSA and free PSA correlated with each other for both groups. Receivers Operating Curve (ROC) analysis indicated a better sensitivity to specificity ratio for PSA/IGF-1 than for PSA or Free/Total (F/T) PSA.

Background: Osteoblasts and osteoblast-derived survival growth factors, such as insulin-like growth factor I (IGF I), inhibit chemotherapy apoptosis of prostate cancer cells, thereby producing cytotoxic drug-resistant tumor growth, in vitro., Methods: We tested a novel therapeutic approach, referred to as antisurvival factor (AFS) therapy, that aimed at reduction of osteoblast-derived IGFs, using dexamethasone (4 mg per os, qD) and growth hormone (GH)-dependent liver-derived IGFs, using a somatostatin-analog (lanreotide, 30 mg, intramuscularly (i.m.), q14D) in combination with triptorelin (3.75 mg, intramuscularly, q28D) to produce a clinical response in 4 patients with progressing hormone-refractory prostate cancer., Results: The patients given ASF therapy exhibited an excellent improvement of clinical performance and a decline of prostate-specific antigen (PSA) within 2 months of ASF therapy. One of them experienced excellent clinical response (normalization of PSA), two experienced good clinical response (decline of PSA of more than 50%), and one experienced stabilization (decline of PSA of less than 50%)., Conclusions: We conclude that this novel concept of combination therapy, using ASF with hormone ablation, is a promising salvage therapy that should be further assessed with a randomized clinical trial.

The ultrastructural morphology of the noninvolved urothelium of tumor-bearing patients before and after interferon-alpha 2b (IFN-alpha 2b) treatment was investigated. The ultrastructure of the normal bladder urothelium has been reported. The noninvolved urothelium of our patients already showed deviation from the normal. At the end of therapy, we noted a partial restoration of the urothelium to its normal morphology with the reestablishment of some of its normal features, i.e., a well-developed Golgi apparatus, the existence of parts of the asymmetric unit membrane, and the appearance of nuclear bodies. Prevention of tumor recurrence by restoring the ultrastructural morphology of the noninvolved urothelium with IFN-alpha 2b is a subject worthy of further investigation.