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The Japanese beetle (JB) Popillia japonica (Newman), has been detected for the first time in Northern Italy in 2014. This alien species is spreading fast Eastwards and Westwards, and this calls for mandatory restrictions within infested areas. To forecast spreading dynamics of P. japonica over years, an iterative spatially based model was conceived and developed. Five years of trapping data by the Regional Plant Protection Organization (RPPO) of Lombardy region were used to build up the model: 2015-2016 observations were used for model parametrization; 2017-2019 for validation. Model includes: a source dilution factor (SF) describing the rate of P. japonica moving away from a given position, based upon variograms; a value G, quantifying the increase in P. japonica population at the same location along years; a mortality factor (MF) based on literature data; three land cover classes quantifying the probability of colonization of new areas. The model proved to perform from fair to good; validation showed that determination coefficient (R2) ranged between 0.39 and 0.87. Variograms from both trapping data and model simulations, suggested a range of spatial autocorrelation of P. japonica ranging from 7.5 to 15 km. Prediction maps indicate a potential spread of P. japonica mainly Southwards and South-eastwards, matching the distribution of suitable land covers (e.g. meadows, croplands, woods). As a result, this model can be retained operationally useful to predict the spread of P. japonica year-per-year, although a periodic/continuous calibration with new field data is suggested.

Purpose: The purpose of the present study was to investigate the perfusion density (PD) of macular superficial (SCP) and deep capillary plexus (DCP), the size of foveal avascular zone (FAZ) and central macular thickness (CMT) in healthy children using optical coherence tomography angiography (OCT-A).Patients and methods: About 206 eyes of 111 children were analyzed. The correlation of gestational age (GA), birth weight (BW), age, sex, refractive errors, and visual acuity (VA) with OCT-A parameters were investigated.Results: The mean PD of the fovea and the mean FAZ area of SCP were 17.1% (DS: 4.26) and 234.47 (DS: 106.39) µm2. The mean PD of the fovea and the mean FAZ area of DCP were 13.5% (DS: 5.23) and 298.32 (DS: 112.37) µm2. Superficial and deep FAZ areas were not correlated with sex, age, BW, refractive errors, or VA. FAZ area of SCP was correlated with foveal PD (r= −0.76) and with CMT (r= −0.68). FAZ area of DCP was correlated with foveal’s PD (r= −0.61). There was no correlation between CMT and refractive errors.Conclusion: OCT-A may provide a non-invasive and reliable approach to evaluate macular perfusion in children. As the FAZ area, PD, and CMT change during the growth period, we performed established a reference range for different ages.

Background: To date, bariatric surgery has been proposed as the most effective treatment to resolve morbid obesity, a multifactorial chronic disease with an epidemic and increasing tendency. The purpose of this study was to determinate the impact of the laparoscopy on weight loss parameters in morbid obese patients who underwent surgery according to Scopinaro’s biliopancreatic diversion (BPD) and evaluate early and late complications related to the open and laparoscopic approach of this technique. Materials and methods: This is a longitudinal retrospective study in consecutive patients undergoing BPD due to morbid obesity between 1999 and 2015. From 2006 the laparoscopic technique was introduced in our group for obesity surgery. In both approaches, open and laparoscopic surgery, the procedure performed consists of a proximal gastric section with a long Roux-en-Y reconstruction. The following variables were assessed in the two groups: intervention duration (min), estimated blood loss (mL), conversions to open approach (%), preoperative stay, postoperative and global stay (days). Complications were divided into early and late postoperative complications. The early surgical complications were catalogued according to the Clavien–Dindo classification. Results: Two hundred seventy-seven patients were consecutively enrolled and divided in two groups: open BPD and laparoscopic BPD. There were no significant differences in the comparison of the two groups and the mean age was 43.9 years (19–60) with a mean BMI of 52.5 kg/m2. A statistically significant reduction was observed in favor of the laparoscopic group with respect to the reduction in hospital stay and in the incidence of incisional hernia as a late complication. No statistically significant difference were found with respect to early postoperative complications. Conclusions: Laparoscopic BPD is a safe technique that allows a shorter hospital stay compared to open surgery and that allows a drastic reduction in the incidence of incisional hernias.

Perioperative myocardial dysfunction occurs frequently in cardiac surgery, and is a risk factor for morbidity and mortality. Levosimendan has been suggested to reduce mortality of patients with perioperative myocardial dysfunction. However, long-term outcome data on its efficacy in cardiac surgery are lacking.

Objective: Rectal schwannomas are extremely rare tumors and their surgical treatment is widely variable in literature. Transanal endoscopic microsurgery (TEM) approach could be a reasonable option for such lesions, offering an organ-sparing strategy, but evidence is scarce.Methods: We report a 69-year-old man with a rectal submucosal lesion at 10 cm from the anal verge, treated by TEM. A systematic literature review on surgical approaches in rectal schwannoma was performed.Results: The patient was successfully treated by TEM, with adequate excision of the submucosal lesion. Histopathology revealed a rectal schwannoma. No recurrence was found at 1-year endoscopic follow-up. Previous studies reported 23 cases of rectal schwannoma and several treatment options, but only 2 cases were treated by TEM. Anterior rectal resection was generally adopted in cases of large, symptomatic masses with inconclusive preoperative biopsy, while lesions with features suggestive of stromal tumors were preferentially treated by endoscopy or, if located in distal rectum, by transanal approaches.Conclusions: An organ-sparing minimally invasive approach should be the standard of care for rectal schwannomas. TEM could extend the indication for their endoscopic treatment, providing adequate excision even for larger schwannomas of the middle–upper rectum.

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Microsurgeons have today the freedom of the “chosen flap”, as opposed to the the “flap of choice”, but the preoperative knowledge of the microanatomy of each patient is mandatory. The needing of preoperative evaluation the perforators, not only in terms of position, but also for dimensions, flow, and relationship with the sorrounding structures became essential and allows more personalized reconstruction, less invasiveness, more safety and finally increase microsurgeon creativity. Ultrasound represents an almost essential armamentarium in the hand of the microsurgeon as it allows a in-depth preoperative evaluation of flap donor-site and a precise planning based on perforator features, including the harvesting of thin, superthin and pureskin perforator flaps.

Introduction:Isatuximab (Isa), a humanized monoclonal antibody directed against the surface antigen CD38, has been available in Italy since October 2021 for the treatment of relapsed or refractory Multiple Myeloma (RRMM) in combination with Pomalidomide (P) and Dexamethasone (d) (IsaPd) after two lines of therapy with lenalidomide and a proteosome inhibitor, and from April 2022 in combination with carfilzomib (K) after one line of treatment. Patients eligible for these therapies must not be refractory to Daratumumab. Here, we report preliminary efficacy and safety data for Isatuximab in a Sardinian study of RRMM patients treated with IsaPd and IsaKda as salvage therapy outside of controlled clinical trials. The primary objective of this study was to evaluate the toxicity profile and quality of response to Isatuximab-based regimens administered as salvage therapy in a real-world setting.

Currently, minimally invasive cardiac surgery (MICS) has been developing and has been largely approved for mitral valve surgery. The more development of MICS, the more the entire surgical setup needs to be appropriate. We developed a homemade tool for mitral annular sizing that is simple and fits the mini surgical access. It is a plastic-based foldable paper that can be easily inserted through the minithoracotomy, using a surgical forceps.

El uso de la fluorescencia en cirugía se ha ampliado y difundido en los últimos años, lo que ha constituido un auténtico fenómeno tecnológico ligado a la aparición de dispositivos adaptados a su utilización en los abordajes laparoscópicos y robóticos. La cirugía guiada por fluorescencia en el campo de la cirugía endocrina está igualmente en auge. Cada vez son más los artículos que describen su uso en la cirugía de las glándulas tiroides, paratiroides y suprarrenal, aunque con series aun modestas y con protocolos diversos no estandarizados. Existen actualmente diversas áreas de desarrollo de la aplicación de la fluorescencia en cirugía endocrina. Cabe destacar el uso de la fluorescencia con verde de indocianina en cirugía suprarrenal, la identificación y predicción de la perfusión paratiroidea con verde de indocianina, y la autofluorescencia de las glándulas paratiroides. El objetivo de este artículo es revisar las actuales aplicaciones de la fluorescencia en cirugía endocrina.

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In DNA repair, the resection of double-strand breaks dictates the choice between homology-directed repair—which requires a 3′ overhang—and classical non-homologous end joining, which can join unresected ends1,2. BRCA1-mutant cancers show minimal resection of double-strand breaks, which renders them deficient in homology-directed repair and sensitive to inhibitors of poly(ADP-ribose) polymerase 1 (PARP1)3–8. When BRCA1 is absent, the resection of double-strand breaks is thought to be prevented by 53BP1, RIF1 and the REV7–SHLD1–SHLD2–SHLD3 (shieldin) complex, and loss of these factors diminishes sensitivity to PARP1 inhibitors4,6–9. Here we address the mechanism by which 53BP1–RIF1–shieldin regulates the generation of recombinogenic 3′ overhangs. We report that CTC1–STN1–TEN1 (CST)10, a complex similar to replication protein A that functions as an accessory factor of polymerase-α (Polα)–primase11, is a downstream effector in the 53BP1 pathway. CST interacts with shieldin and localizes with Polα to sites of DNA damage in a 53BP1- and shieldin-dependent manner. As with loss of 53BP1, RIF1 or shieldin, the depletion of CST leads to increased resection. In BRCA1-deficient cells, CST blocks RAD51 loading and promotes the efficacy of PARP1 inhibitors. In addition, Polα inhibition diminishes the effect of PARP1 inhibitors. These data suggest that CST–Polα-mediated fill-in helps to control the repair of double-strand breaks by 53BP1, RIF1 and shieldin. 53BP1 and shieldin recruit the CTC1–STN1–TEN1 complex and polymerase-α to sites of DNA damage to help control the repair of double-strand breaks.

CNS/Reuters/Alessandro Bianchi Like many Catholic parishes, the Vatican has turned to a raffle to raise money: the difference is that the prizes are items originally given as gifts to Pope [...]

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The firing of eukaryotic origins of DNA replication requires CDK and DDK kinase activities. DDK, in particular, is involved in setting the temporal program of origin activation, a conserved feature of eukaryotes. Rif1, originally identified as a telomeric protein, was recently implicated in specifying replication timing in yeast and mammals. We show that this function of Rif1 depends on its interaction with PP1 phosphatases. Mutations of two PP1 docking motifs in Rif1 lead to early replication of telomeres in budding yeast and misregulation of origin firing in fission yeast. Several lines of evidence indicate that Rif1/PP1 counteract DDK activity on the replicative MCM helicase. Our data suggest that the PP1/Rif1 interaction is downregulated by the phosphorylation of Rif1, most likely by CDK/DDK. These findings elucidate the mechanism of action of Rif1 in the control of DNA replication and demonstrate a role of PP1 phosphatases in the regulation of origin firing.

BAF180, a subunit of the PBAF chromatin remodeling complex, is frequently mutated in cancer. Although PBAF regulates transcription, it remains unclear whether this is what drives tumorigenesis in cells lacking BAF180. Based on data from yeast, we hypothesized that BAF180 may prevent tumorigenesis by promoting cohesion. Here, we show BAF180 is required for centromeric cohesion in mouse and human cells. Mutations identified in tumor samples are unable to support this activity, and also compromise cohesion-dependent functions in yeast. We provide evidence of genome instability in line with loss of cohesion, and importantly, we find dynamic chromosome instability following DNA damage in cells lacking BAF180. These data demonstrate a function for BAF180 in promoting genome stability that is distinct from its well-characterized role in transcriptional regulation, uncovering a potent mechanism for its tumor-suppressor activity.

Seven classes of mitogen-activated protein kinase (MAPK) intracellular signalling cascades exist, four of which are implicated in breast disease and function in mammary epithelial cells. These are the extracellular regulated kinase (ERK)1/2 pathway, the ERK5 pathway, the p38 pathway and the c-Jun N-terminal kinase (JNK) pathway. In some forms of human breast cancer and in many experimental models of breast cancer progression, signalling through the ERK1/2 pathway, in particular, has been implicated as being important. We review the influence of ERK1/2 activity on the organised three-dimensional association of mammary epithelial cells, and in models of breast cancer cell invasion. We assess the importance of epidermal growth factor receptor family signalling through ERK1/2 in models of breast cancer progression and the influence of ERK1/2 on its substrate, the oestrogen receptor, in this context. In parallel, we consider the importance of these MAPK-centred signalling cascades during the cycle of mammary gland development. Although less extensively studied, we highlight the instances of signalling through the p38, JNK and ERK5 pathways involved in breast cancer progression and mammary gland development.

Heat shock proteins (HSPs) are potent inducers of an antigen‐specific immunological response. A role of chaperon of immunogenic peptides and a direct effect on APC activation and function have been described. However, the signal transduction events involved in the activation of human APCs are poorly characterized. We investigated, using human monocyte‐derived dendritic cells (DCs), the signal transduction pathways activated by a human recombinant HSP70 (r)HSP70 purified from eukaryotic cells. rHSP70 effectively induced a partial maturation of DCs in vitro and a significant increase in the titers of antigen‐specific IgG when used as a vaccine adjuvant in vivo. rHSP70 did not desensitize human DCs to LPS stimulation and retained its adjuvant properties in C3H/HeJ mice, which are LPS‐resistant as a result of a mutation in TLR‐4, ruling out the potential interference of LPS contamination. Effects on DC maturation and in vivo functions correlate to the ability of rHSP70 to activate IκB‐α/NF‐κB and ERK1/2 pathways in human DCs. No activation of p38 was induced in the same experimental conditions. Our data suggest that the IκB‐α/NF‐κB pathway has a critical role in the partial maturation of DCs induced by rHSP70.

Rap1p, the major telomere repeat binding protein in yeast, has been implicated in both de novo telomere formation and telomere length regulation. To characterize the role of Rap1p in these processes in more detail, we studied the generation of telomeres in vivo from linear DNA substrates containing defined arrays of Rap1p binding sites. Consistent with previous work, our results indicate that synthetic Rap1p binding sites within the internal half of a telomeric array are recognized as an integral part of the telomere complex in an orientation-independent manner that is largely insensitive to the precise spacing between adjacent sites. By extending the lengths of these constructs, we found that several different Rap1p site arrays could never be found at the very distal end of a telomere, even when correctly oriented. Instead, these synthetic arrays were always followed by a short (≈100-bp) “cap” of genuine TG repeat sequence, indicating a remarkably strict sequence requirement for an end-specific function(s) of the telomere. Despite this fact, even misoriented Rap1p site arrays promote telomere formation when they are placed at the distal end of a telomere-healing substrate, provided that at least a single correctly oriented site is present within the array. Surprisingly, these heterogeneous arrays of Rap1p binding sites generate telomeres through a RAD52-dependent fusion resolution reaction that results in an inversion of the original array. Our results provide new insights into the nature of telomere end capping and reveal one way by which recombination can resolve a defect in this process.

Several advanced nuclear plant concepts are characterized by the use of innovative cooling systems that remove the heat released inside the containment following a hypothetical accident, such as a loss-of-coolant accident, through passive heat transfer mechanisms. The design and installation of a localized passive containment cooling system (PCCS) inside a double-wall concrete containment requires the reliable knowledge of temporal and spatial distribution of noncondensable gas concentration, especially hydrogen, in a multicompartment geometry. Testing was conducted in the Large-Scale Containment Test Facility located at the Westinghouse Science and Technology Center in Pittsburgh, and the testing was modified to simulate in approximately one-tenth scale the main features of a concrete containment, designed by the Italian National Electric Utility (ENEL), in which the heat is removed through internal heat exchangers (HX) located in the dome region, and connected by an intermediate fluid loop to external HXs placed outside the double barrier concrete containment. No active component like pumps or human intervention are required for the operation of the system. The facility instrumentation, the test program, and the experimental results are described along with the first results obtained in the application of the FUMO code to the analysis of these experimental tests. The experimental data measured during the tests include temperature distributions inside the containment, helium concentrations at four internal locations, and laser Doppler anemometer measures to determine the atmosphere mixing under different simulated accident conditions. The experimental results indicate that helium, which simulates the hydrogen that may be released during some accident sequences, is distributed rather homogeneously inside the facility. The very good mixing exhibited by the helium indicates that the localized PCCS induces efficient convective motions inside the containment atmosphere, and this is a positive indication for safety analysis.

Telomere length in human cells is controlled by a homeostasis mechanism that involves telomerase and the negative regulator of telomere length, TRF1 (TTAGGG repeat binding factor 1). Here we report that TRF2, a TRF1-related protein previously implicated in protection of chromosome ends, is a second negative regulator of telomere length. Overexpression of TRF2 results in the progressive shortening of telomere length, similar to the phenotype observed with TRF1. However, while induction of TRF1 could be maintained over more than 300 population doublings and resulted in stable, short telomeres, the expression of exogenous TRF2 was extinguished and the telomeres eventually regained their original length. Consistent with their role in measuring telomere length, indirect immunofluorescence indicated that both TRF1 and TRF2 bind to duplex telomeric DNA in vivo and are more abundant on telomeres with long TTAGGG repeat tracts. Neither TRF1 nor TRF2 affected the expression level of telomerase. Furthermore, the presence of TRF1 or TRF2 on a short linear telomerase substrate did not inhibit the enzymatic activity of telomerase in vitro. These findings are consistent with the recently proposed t loop model of telomere length homeostasis in which telomerase-dependent telomere elongation is blocked by sequestration of the 3′ telomere terminus in TRF1- and TRF2-induced telomeric loops.

Ku is a heterodimeric protein with high binding affinity for ends, nicks, and gaps in double-stranded DNA. Both in mammalian cells and in budding yeast, Ku plays a role in nonhomologous end joining in the double strand break repair pathway. However, Ku has a more significant role in DNA repair in mammalian cells compared with yeast, in which a homology-dependent pathway is the predominant one. Recently Ku has been shown to be a likely component of the telomeric complex in yeast, suggesting the possibility of a similar role for Ku at mammalian telomeres. However, long single-stranded G-rich overhangs are continuously present at mammalian but not at yeast telomeres. These overhangs have the potential to fold in vitrointo G-G base-paired conformations, such as G-quartets, that might prevent Ku from recognizing telomeric ends and thus offer a mechanism to sequester the telomere from the prevalent double strand break repair pathway in mammals. We show here that Ku binds to mammalian telomeric DNA ends in vitroand that G-quartet conformations are unable to prevent Ku from binding with high affinity to the DNA. Our results indicate that the DNA binding characteristics of Ku are consistent with its direct interaction with telomeric DNA in mammalian cells and its proposed role as a telomere end factor.

Our study belongs to the clinical trials in which the health-related quality of life (HQL) evaluation constitutes the primary endpoint. It was carried out with the aim of comparing the impact of three different types of psychological intervention, namely a psychopharmacological treatment alone, the same treatment plus social support carried out by volunteers (SSV) and a third treatment modality including “structured psychotherapy” (autogenous training), on improving the HQL of elderly cancer patients undergoing antineoplastic therapy with symptoms of anxiety and/or depression related to their disease. The eight questionnaires used for HQL evaluation were generally. self-rated and multidimensional but unidimensional models were also employed. Seventy-four patients aged over 65 years with either solid tumors in different sites or hematological malignancies, generally in advanced stages (III–IV), were enrolled in the study. Of these patients, 72 (42 men and 30 women, mean age 70.68 years, range 66–85) were evaluable. Our study high-lighted the usefulness of the pharmacological therapy (alprazolam + sulpiride) and of other specific ancillary treatments in reducing the incidence of the main HQL-related side-effects of antineoplastic therapy and the superiority of an “integrated” strategy, based both on psychopharmacology and psychosocial interventions, such as SSV with or without structured psychotherapy. The one-way analysis of variance carried out by us did not allow us to draw definitive conclusions about which of the two integrated treatments was to be considered the treatment of choice, as they proved to be almost equally effective.

A cluster of four Azospirillum brasilense histidine biosynthetic genes, hisA, hisB, hisF and hisH, was identified on a 4.5 kb DNA fragment and its organization studied by complementation analysis of Escherichia coli mutations and nucleotide sequence. The nucleotide sequence of a 1.3 kb fragment that complemented the E. coli hisB mutation was determined and an ORF of 624 nucleotides which can code for a protein of 207 amino acids was identified. A significant base sequence homology with the carboxyterminal moiety of the E. coli hisB gene (0.53) and the Saccharomyces cerevisiae HIS3 gene (0.44), coding for an imidazole glycerolphosphate dehydratase activity was found. The amino acid sequence and composition, the hydropathic profile and the predicted secondary structures of the yeast, E. coli and A. brasilense proteins were compared. The significance of the data presented is discussed.

We carried out a pilot nonrandomized phase II study to compare the neo-adjuvant chemotherapic regimen with cisplatin, 5-FU and vinorelbine with the same combination plus s.c. IL 2 in advanced head and neck squamous cell carcinoma (HNSCC). The primary goals of the trial were to evaluate the feasibility and response rates of the two regimens. The study design consisted of a patient's assignment to either of the two following arms: Arm A: Cisplatin 80 mg/m2 i.v. on day 1; 5-FU 600 mg/m2 i.v. on days 2–5; and vinorelbine 20 mg/m2 i.v. on days 2 and 8, Arm B: the same chemotherapic regimen plus recombinant IL 2 (Proleukin, Eurocetus) 9 MIU s.c. daily from day 9 to 13 and from day 16 to 20 for every cycle. From March 1993 to November 1993 twenty three patients with Stage III–IV HNSCC were enrolled in the study. Patients could be evaluated for response to treatment if they had received at least 2 complete cycles of therapy. The overall response rate (ORR) was 63% in Arm A and 100% in Arm B. The differences for ORR and CR rates were statistically significant in favor of Arm B. The analysis for each of the three drugs included in the chemotherapy schedule shows that both the actually received average dose-intensity and the actually delivered average cumulative doses/patient were higher for Arm B (chemo- plus IL 2 therapy) (approximately 80% of programmed dose-intensity) than for Arm A (approximately 70% of programmed dose-intensity). Both the actually received average dose-intensity and the actually delivered average cumulative doses/patient for IL 2 were more than 80%. In both arms the most frequent side effects were myelosuppression, phlebitis and electrolyte disturbances. There were 2 toxic deaths, 1 in Arm A and 1 in Arm B, both for hematologic toxicity. Our “pilot” study suggests that the combination of cisplatin, 5-FU, vinorelbine plus IL 2 is a highly active, but rather toxic, neo-adjuvant treatment in advanced HNSCC with very high ORR and CR rates.

Human telomeres consist of long arrays of TTAGGG repeats bound to the telomere-specific proteins, TRF1 and TRF2. Here we describe the structure of in vitro complexes formed between telomeric DNA and TRF1 as deduced by electron microscopy. Visualization of TRF1 bound to DNA containing six or 12 tandem TTAGGG repeats revealed a population of DNAs containing a spherical protein complex localized just to the repeats. Mass analysis of the protein complexes suggested binding of TRF1 dimers and tetramers to the TTAGGG repeats. The DNA was not significantly compacted or extended by protein binding. TRF1 formed filamentous structures on longer telomeric repeat arrays (≥27 repeats) consistent with the presence of an array of bound TRF1 dimers. Unexpectedly, there was a strong propensity for two telomeric tracts to form paired synapses over the TRF1 covered segment. Up to 30% of the TRF1-bound DNAs could be found in a paired configuration with a strong bias for a parallel as contrasted to an antiparallel arrangement. TRF1-induced pairing was confirmed using a ligation assay which detected the formation of DNA multimers dependent on the presence of TRF1 and a 27mer repeat array in the DNA. These findings suggests that this protein may have an architectural role at telomeres. We discuss the possibility that TRF1-dependent changes in the conformation of telomeres are involved in the regulation of telomere length.

Abstract: We carried out an open, randomized, phase III, multicenter clinical trial to compare, in neo-adjuvant setting, the clinical response and toxicity of the combination chemotherapy cisplatin + 5-FU with the same combination plus s.c. recombinant interleukin-2 (rIL-2) in patients with advanced (stage III–IV) head and neck squamous-cell carcinoma (HNSCC). Regimen A was the classical Al Sarraf treatment: 100 mg/m2 cisplatin i.v. on day 1 plus 1000 mg m−2 day−1 5-FU on days 1–5 as a continuous infusion. Regimen B was the same as regimen A plus 4.5 MIU/day rIL-2 s.c. on days 8–12 and 15–19. Treatment was repeated every 3 weeks for three cycles. A total of 33 patients were enrolled in the study; 30 were evaluable for toxicity and 28 for response. Seventeen patients were assigned to group A and 16 were assigned to group B. Three patients (20%) of group A and 4 (31%) of group B had a complete response, 9 patients (60%) of group A and 6 (46%) of group B had a partial response, with an overall response rate of 12 patients (80%) for group A and 10 patients (77%) for group B. Two patients (13%) of group A and 3 patients (23%) group B had stable disease; 1 patient (7%) of group A had progressive disease. Thus, there was not a statistically significant difference in response rate between the two groups and therefore there was no benefit from the addition of immunotherapy with rIL-2 to the standard chemotherapy. Both regimens were well tolerated. There were 2 toxic deaths (6.7%), 1 from hematological causes in group A and 1 from cardiac causes in group B. Myelosuppression and gastrointestinal toxicity, mainly nausea/vomiting and stomatitis, were the most frequent toxicities. The calculated number of patients for the sample has not yet been reached; however, the projection of our present results suggests that it is highly improbable that a clinically significant difference between the two treatment groups will be observed even if the calculated patient sample size is achieved.

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The article presents an interview with philosopher Andre Vltchek who discusses the candidacy of U.S. presidential candidate Donald Trump, the impact of the growth of expansionism of the U.S. to a collision with China, and the role of human rights non-governmental organizations.