Improved overall survival in patients developing endocrine toxicity during treatment with nivolumab for advanced non-small cell lung cancer in a prospective study.

PURPOSE: Immune checkpoint inhibitors (ICPIs) disrupting PD-1/PD-L1 axis have revolutionized the management of advanced non-small cell lung cancer (NSCLC). Some studies identified the development of endocrine toxicity as predictor of better survival in cancer patients treated with ICPIs. The aim of study was to evaluate survival and new onset of immune-related endocrine adverse events (irAEs) in patients treated with nivolumab for advanced NSCLC. METHODS: In a prospective study, 73 patients with previously treated advanced NSCLC received nivolumab in monotherapy. Blood samples were collected at each cycle to monitor thyroid autoimmunity, thyroid, adrenal and somatotroph axes, while thyroid morphology was evaluated by ultrasonography. RESULTS: An impaired thyroid function was recorded in 23.4% of patients (n = 15). Eight patients developed asymptomatic transient thyrotoxicosis (ATT) evolving to hypothyroidism in 50% of cases. In addition, seven patients developed overt hypothyroidism without ATT and with negative autoantibodies. Patients who developed hypothyroidism proved to have better overall survival (OS) as compared with non-developers at both univariate (p = 0.021) and multivariate analyses (p = 0.023). The survival curve of patients with reduced IGF-I at baseline, or displaying its reduction during the follow-up, showed significantly reduced median survival compared to patients with normal/high IGF-I levels (p = 0.031). CONCLUSIONS: Thyroid function abnormalities are the major irAEs in patients treated with nivolumab, and hypothyroidism onset is associated with prolonged survival. Our findings indicate that the development of hypothyroidism is a positive predictive biomarker of nivolumab antitumor efficacy in patients with NSCLC. Low IGF-I levels could represent a negative prognostic factor during nivolumab therapy.

Sporadic non-functioning pancreatic neuroendocrine tumours: multicentre analysis.

BACKGROUND: Outcomes after surgery for sporadic pancreatic neuroendocrine neoplasms (Pan-NENs) were evaluated. METHODS: This multicentre study included patients who underwent radical pancreatic resection for sporadic non-functioning Pan-NENs. In survival analysis, the risk of mortality in this cohort was analysed in relation to that of the matched healthy Italian population. Relative survival (RS) was calculated as the rate between observed and expected survival. Factors related to RS were investigated using multivariable modelling. RESULTS: Among 964 patients who had pancreatic resection for sporadic non-functioning Pan-NENs, the overall RS rate was 91.8 (95 per cent c.i. 81.5 to 96.5) per cent. 2019 WHO grade (hazard ratio (HR) 5.75 (s.e. 4.63); P = 0.030) and European Neuroendocrine Tumour Society (ENETS) TNM stage (6.73 (3.61); P < 0.001) were independent predictors of RS. The probability of a normal lifespan for patients with G1, G2, G3 Pan-NENS, and pancreatic neuroendocrine carcinomas (Pan-NECs) was 96.7, 54.8, 0, and 0 per cent respectively. The probability of a normal lifespan was 99.8, 99.3, 79.8, and 46.8 per cent for those with stage I, II, III, and IV disease respectively. The overall disease-free RS rate was 73.6 (65.2 to 79.5) per cent. 2019 WHO grade (HR 2.10 (0.19); P < 0.001) and ENETS TNM stage (HR 2.50 (0.24); P < 0.001) significantly influenced disease-free RS. The probability of disease-free survival was 93.2, 84.9, 45.2, and 6.8 per cent for patients with stage I, II, III, and IV disease, and 91.9, 45.2, 9.4, and 0.7 per cent for those with G1, G2, G3 Pan-NENS, and Pan-NECs, respectively. CONCLUSION: A surgical approach seems without benefit for Pan-NECs, and unnecessary for small G1 sporadic Pan-NENs. Surgery alone may be insufficient for stage III-IV and G3 Pan-NENs.

Risk of preoperative understaging of duodenal neuroendocrine neoplasms: a plea for caution in the treatment strategy.

PURPOSE: Pretreatment staging is the milestone for planning either surgical or endoscopic treatment in duodenal neuroendocrine neoplasms (dNENs). Herein, a series of surgically treated dNEN patients was evaluated to assess the concordance between the pre- and postsurgical staging. METHODS: Retrospective analysis of patients with a histologically confirmed diagnosis of dNENs, who underwent surgical resection observed at eight Italian tertiary referral centers. The presurgical TNM stage, based on the radiological and functional imaging, was compared with the pathological TNM stage, after surgery. RESULTS: From 2000 to 2019, 109 patients were included. Sixty-six patients had G1, 26 a G2, 7 a G3 dNEN (Ki-67 not available in 10 patients). In 46/109 patients (42%) there was disagreement between the pre- and postsurgical staging, being it understaged in 42 patients (38%), overstaged in 4 (3%). As regards understaging, in 25 patients (22.9%), metastatic loco-regional nodes (N) resulted undetected at both radiological and functional imaging. Understaging due to the presence of distal micrometastases (M) was observed in 2 cases (1.8%). Underestimation of tumor extent (T) was observed in 12 patients (11%); in three cases the tumor was understaged both in T and N extent. CONCLUSIONS: Conventional imaging has a poor detection rate for loco-regional nodes and micrometastases in the presurgical setting of the dNENs. These results represent important advice when local conservative approaches, such as endoscopy or local surgical excision are considered and it represents a strong recommendation to include endoscopic ultrasound in the preoperative tools for a more accurate local staging.

Impact of the SARS-CoV2 pandemic dissemination on the management of neuroendocrine neoplasia in Italy: a report from the Italian Association for Neuroendocrine Tumors (Itanet).

INTRODUCTION: The organization of the healthcare system has significantly changed after the recent COVID-19 outbreak, with a negative impact on the management of oncological patients. The present survey reports data collected by the Italian Association for Neuroendocrine Tumors on the management of patients with neuroendocrine neoplasia (NEN) during the pandemic dissemination. METHODS: A survey with 57 questions was sent to NEN-dedicated Italian centers regarding the management of patients in the period March 9, 2020, to May 9, 2020 RESULTS: The main modification in the centers' activity consisted of decreases in newly diagnosed NEN patients (- 76.8%), decreases in performed surgical procedures (- 58%), delays to starting peptide receptor radionuclide therapy (45.5%), postponed/canceled follow-up examinations (26%), and canceled multidisciplinary teams' activity (20.8%). A low proportion of centers (< 10%) reported having to withdraw systemic anti-tumor medical treatment due to concerns about the pandemic situation, whereas PRRT was withdrawn from no patients. CONCLUSION: Although the COVID-19 outbreak induced the centers to reduce some important activities in the management of NEN patients, the Italian network was able to provide continuity in care without withdrawing anti-tumor treatment for the majority of patients.

The functioning side of the pancreas: a review on insulinomas.

PURPOSE: Insulinomas are a rare type of neuroendocrine tumors, originating in the pancreas, difficult to diagnose and to treat. Due to its rarity, insulinomas are a not well-known pathological entity; thus, the diagnostic process is frequently a medical challenge with many possible differential diagnoses. The diagnostic process varies between non-invasive procedures, such as the fasting test or imaging techniques, and invasive ones. Insulinomas are rarely malignant, but the glycemic imbalance correlated with this tumor can frequently alter the quality of life of the patients and the consequent hypoglycemia can be extremely dangerous. Moreover, insulinomas can be associated with different genetic syndromes, such as Multiple Endocrine Neoplasia 1, accompanied by other specific symptoms. There are many different treatment strategies, depending on the need to control symptoms or control diseases progression, the only curative one being surgery. METHODS AND RESULTS: We reviewed the evidences present in the literature on insulinomas and reported its main clinical characteristics and management strategies. CONCLUSION: The aim of this review of the literature is to present the current knowledge on insulinomas, exploring the main clinical characteristics, the diagnostic tools, and the therapeutic strategies.

Vinasse and Its Influence on Ant (Hymenoptera: Formicidae) Communities in Sugarcane Crops.

Sugarcane is an important crop within the Brazilian socioeconomic landscape. There is a constant need for approaches to increase sustainability at all steps of the production chain. Irrigating sugarcane crops with vinasse is one of these approaches, because vinasse is a residue of sugarcane processing that can be used to fertilize these same crops. However, due to its chemical properties, vinasse may be harmful to soil fauna. Analyzing the structure and functional organization of ant communities is a fast and practical way to monitor sites affected by the addition of chemicals. This study compared the structure of soil ant communities in vinasse-irrigated sugarcane crops to those in secondary forests adjacent to the crops. In total, 32 genera and 107 species of ants were observed; of these, 30 species foraged in crop fields and 102 foraged in forests. Twenty-five percent of the species were present in both crops and forests. Ant communities in crop soil had poorer taxonomic composition and lower richness in each functional group compared to communities in forest remnants. However, regardless of vegetation type, epigeic ants were more diverse, and Dorymyrmex brunneus (crop) and Pachycondyla striata (forest) were very frequent. Vinasse did not increase the diversity of epigeic and hypogeic ants, but it may affect the community composition.

Time Dependence of the Electron and Positron Components of the Cosmic Radiation Measured by the PAMELA Experiment between July 2006 and December 2015.

Cosmic-ray electrons and positrons are a unique probe of the propagation of cosmic rays as well as of the nature and distribution of particle sources in our Galaxy. Recent measurements of these particles are challenging our basic understanding of the mechanisms of production, acceleration, and propagation of cosmic rays. Particularly striking are the differences between the low energy results collected by the space-borne PAMELA and AMS-02 experiments and older measurements pointing to sign-charge dependence of the solar modulation of cosmic-ray spectra. The PAMELA experiment has been measuring the time variation of the positron and electron intensity at Earth from July 2006 to December 2015 covering the period for the minimum of solar cycle 23 (2006-2009) until the middle of the maximum of solar cycle 24, through the polarity reversal of the heliospheric magnetic field which took place between 2013 and 2014. The positron to electron ratio measured in this time period clearly shows a sign-charge dependence of the solar modulation introduced by particle drifts. These results provide the first clear and continuous observation of how drift effects on solar modulation have unfolded with time from solar minimum to solar maximum and their dependence on the particle rigidity and the cyclic polarity of the solar magnetic field.

New upper limit on strange quark matter abundance in cosmic rays with the PAMELA space experiment.

In this work we present results of a direct search for strange quark matter (SQM) in cosmic rays with the PAMELA space spectrometer. If this state of matter exists it may be present in cosmic rays as particles, called strangelets, having a high density and an anomalously high mass-to-charge (A/Z) ratio. A direct search in space is complementary to those from ground-based spectrometers. Furthermore, it has the advantage of being potentially capable of directly identifying these particles, without any assumption on their interaction model with Earth's atmosphere and the long-term stability in terrestrial and lunar rocks. In the rigidity range from 1.0 to ∼1.0×10^{3} GV, no such particles were found in the data collected by PAMELA between 2006 and 2009. An upper limit on the strangelet flux in cosmic rays was therefore set for particles with charge 1≤Z≤8 and mass 4≤A≤1.2×10^{5}. This limit as a function of mass and as a function of magnetic rigidity allows us to constrain models of SQM production and propagation in the Galaxy.

An anomalous positron abundance in cosmic rays with energies 1.5-100 GeV.

Antiparticles account for a small fraction of cosmic rays and are known to be produced in interactions between cosmic-ray nuclei and atoms in the interstellar medium, which is referred to as a 'secondary source'. Positrons might also originate in objects such as pulsars and microquasars or through dark matter annihilation, which would be 'primary sources'. Previous statistically limited measurements of the ratio of positron and electron fluxes have been interpreted as evidence for a primary source for the positrons, as has an increase in the total electron+positron flux at energies between 300 and 600 GeV (ref. 8). Here we report a measurement of the positron fraction in the energy range 1.5-100 GeV. We find that the positron fraction increases sharply over much of that range, in a way that appears to be completely inconsistent with secondary sources. We therefore conclude that a primary source, be it an astrophysical object or dark matter annihilation, is necessary.

Results of treatment of advanced-stage lymphoblastic lymphoma at St Jude Children's Research Hospital from 1962 to 2002.

BACKGROUND: Reliable prognostic factors have not been established for advanced-stage pediatric lymphoblastic lymphoma (LL). We analyzed treatment outcomes and potential risk factors in children and adolescents with advanced-stage LL treated over a 40-year period. PATIENTS AND METHODS: From 1962 through 2002, 146 patients (99 boys and 47 girls) with stage III (n = 111) or stage IV (n = 35) LL were treated at St Jude Children's Research Hospital. The five treatment eras were 1962-1975 (no protocol), 1975-1979 (NHL-75), 1979-1984 (Total 10 High), 1985-1992 (Pediatric Oncology Group protocol), and 1992-2002 (NHL13). Age at diagnosis was <10 years in 65 patients and ≥10 years in 81. RESULTS: Outcomes improved markedly over successive treatment eras. NHL13 produced the highest 5-year event-free survival (EFS) estimate (82.9% ± 6.1% [SE]) compared with only 20.0% ± 8.0% during the earliest era. Treatment era (P < 0.0001) and age at diagnosis (<10 years versus ≥10 years, P = 0.0153) were independent prognostic factors, whereas disease stage, lactate dehydrogenase level, and presence of a pleural effusion were not. CONCLUSIONS: Treatment era and age were the most important prognostic factors for children with advanced-stage LL. We suggest that a better assessment of early treatment response may help to identify patients with drug-resistant disease who require more intensive therapy.

Cosmic-ray positron energy spectrum measured by PAMELA.

Precision measurements of the positron component in the cosmic radiation provide important information about the propagation of cosmic rays and the nature of particle sources in our Galaxy. The satellite-borne experiment PAMELA has been used to make a new measurement of the cosmic-ray positron flux and fraction that extends previously published measurements up to 300 GeV in kinetic energy. The combined measurements of the cosmic-ray positron energy spectrum and fraction provide a unique tool to constrain interpretation models. During the recent solar minimum activity period from July 2006 to December 2009, approximately 24,500 positrons were observed. The results cannot be easily reconciled with purely secondary production, and additional sources of either astrophysical or exotic origin may be required.

Natural history of gastro-entero-pancreatic and thoracic neuroendocrine tumors. Data from a large prospective and retrospective Italian epidemiological study: the NET management study.

BACKGROUND: The few epidemiological data available in literature on neuroendocrine tumors (NET) are mainly based on Registry databases, missing therefore details on their clinical and natural history. AIM: To investigate epidemiology, clinical presentation, and natural history of NET. DESIGN AND SETTING: A large national retrospective survey was conducted in 13 Italian referral centers. Among 1203 NET, 820 originating in the thorax (T-NET), in the gastro-enteropancreatic tract (GEP-NET) or metastatic NET of unknown primary origin (U-NET) were enrolled in the study. RESULTS: 93% had a sporadic and 7% a multiple endocrine neoplasia type 1 (MEN1)-associated tumor; 63% were GEP-NET, 33% T-NET, 4% U-NET. Pancreas and lung were the commonest primary sites. Poorly differentiated carcinomas were <10%, all sporadic. The incidence of NET had a linear increase from 1990 to 2007 in all the centers. The mean age at diagnosis was 60.0 ± 16.4 yr, significantly anticipated in MEN1 patients (47.7 ± 16.5 yr). Association with cigarette smoking and other non-NET cancer were more prevalent than in the general Italian population. The first symptoms of the disease were related to tumor burden in 46%, endocrine syndrome in 23%, while the diagnosis was fortuity in 29%. Insulin (37%) and serotonin (35%) were the most common hormonal hypersecretions. An advanced tumor stage was found in 42%, more frequently in the gut and thymus. No differences in the overall survival was observed between T-NET and GEP-NET and between sporadic and MEN1-associated tumors at 10 yr from diagnosis, while survival probability was dramatically reduced in U-NET. CONCLUSIONS: The data obtained from this study furnish relevant information on epidemiology, natural history, and clinico-pathological features of NET, not available from the few published Register studies.

A Review of the EUSO-Balloon Pathfinder for the JEM-EUSO Program.

EUSO-Balloon is a pathfinder for JEM-EUSO, the mission concept of a spaceborne observatory which is designed to observe Ultra-High Energy Cosmic Ray (UHECR)-induced Extensive Air Showers (EAS) by detecting their UltraViolet (UV) light tracks "from above." On August 25, 2014, EUSO-Balloon was launched from Timmins Stratospheric Balloon Base (Ontario, Canada) by the balloon division of the French Space Agency CNES. After reaching a floating altitude of 38 km, EUSO-Balloon imaged the UV light in the wavelength range ∼290-500 nm for more than 5 hours using the key technologies of JEM-EUSO. The flight allowed a good understanding of the performance of the detector to be developed, giving insights into possible improvements to be applied to future missions. A detailed measurement of the photoelectron counts in different atmospheric and ground conditions was achieved. By means of the simulation of the instrument response and by assuming atmospheric models, the absolute intensity of diffuse light was estimated. The instrument detected hundreds of laser tracks with similar characteristics to EASs shot by a helicopter flying underneath. These are the first recorded laser tracks measured from a fluorescence detector looking down on the atmosphere. The reconstruction of the direction of the laser tracks was performed. In this work, a review of the main results obtained by EUSO-Balloon is presented as well as implications for future space-based observations of UHECRs.

Natural killer cell engineering for cellular therapy of cancer.

Natural killer (NK) cells can kill transformed cells and represent a promising tool for the treatment of cancer. Their function is governed by a balance of stimulatory and inhibitory signals triggered by surface receptors. Advances in NK cell therapy require the development of dependable methods for obtaining an adequate number of effector cells; additional activation or genetic modification may further increase their anticancer capacity. A method for NK cell expansion used in our laboratory relies on a genetically modified form of the K562 myeloid leukemia cell line, engineered to express a membrane-bound form of interleukin-15 and the ligand for the costimulatory molecule 4-1BB (CD137). Expanded NK cells can be transduced with genes encoding chimeric antigen receptors that stimulate tumor cell-specific cytotoxicity. These methods for NK cell expansion and genetic modification have been adapted to large-scale, clinical-grade, Current Good Manufacturing Practice conditions and support two active clinical trials. Summarized are current efforts for NK cell immunotherapy for cancer and future perspectives.

Cosmic-ray electron flux measured by the PAMELA experiment between 1 and 625 GeV.

Precision measurements of the electron component in the cosmic radiation provide important information about the origin and propagation of cosmic rays in the Galaxy. Here we present new results regarding negatively charged electrons between 1 and 625 GeV performed by the satellite-borne experiment PAMELA. This is the first time that cosmic-ray e⁻ have been identified above 50 GeV. The electron spectrum can be described with a single power-law energy dependence with spectral index -3.18 ± 0.05 above the energy region influenced by the solar wind (> 30 GeV). No significant spectral features are observed and the data can be interpreted in terms of conventional diffusive propagation models. However, the data are also consistent with models including new cosmic-ray sources that could explain the rise in the positron fraction.

Second primary neoplasms in patients with lung and gastroenteropancreatic neuroendocrine neoplasms: Data from a retrospective multi-centric study.

BACKGROUND: Patients with sporadic neuroendocrine neoplasms may exhibit a higher risk of a second primary tumor than the general population. AIM: This study aimed to analyze the occurrence of second primary malignancies. METHODS: A retrospective cohort of 2757 patients with sporadic lung and gastro-entero-pancreatic neuroendocrine neoplasms, managed at eight Italian tertiary referral Centers, was included. RESULTS: Between 2000 and 2019, a second primary malignancy was observed in 271 (9.8%) neuroendocrine neoplasms patients with 32 developing a third tumor. There were 135 (49.8%) females and the median age was 64 years. The most frequent locations of the second tumors were breast (18.8%), prostate (12.5%), colon (9.6%), blood tumors (8.5%), and lung (7.7%). The second primary tumor was synchronous in 19.2% of cases, metachronous in 43.2%, and previous in 37.6%. As concerned the neuroendocrine neoplasms, the 5- and 10-year survival rates were 87.8% and 74.4%, respectively. PFS for patients with a second primary malignancy was shorter than for patients without a second primary malignancy. Death was mainly related to neuroendocrine neoplasms. CONCLUSION: In NEN patients the prevalence of second primary malignancies was not negligible, suggesting a possible neoplastic susceptibility. Overall survival was not affected by the occurrence of a second primary malignancy.

Interferon gamma inhibits apoptotic cell death in B cell chronic lymphocytic leukemia.

The malignant, CD5+ B lymphocytes of B cell chronic lymphocytic leukemia (B-CLL) die by apoptosis in vitro. This is in contrast to the prolonged life span of the leukemic cells in vivo and likely reflects the lack of essential growth factors in the tissue culture medium. We found that interferon gamma (IFN-gamma) inhibits programmed cell death and promotes survival of B-CLL cells in culture. This effect may also be important in vivo: increased serum levels of IFN-gamma, ranging from 60 to > 2,200 pg/ml, were found in 7 of 10 B-CLL samples tested, whereas the sera of 10 healthy individuals did not contain detectable levels of this cytokine (< 20 pg/ml). High levels of IFN-gamma message were detected in RNA from T cell-depleted B-CLL peripheral blood samples by Northern blot analysis. Synthesis of IFN-gamma by B-CLL lymphocytes was confirmed by in situ hybridization and flow cytometry. The majority of B-CLL cells (74-82%) expressed detectable levels of IFN-gamma mRNA, and CD19+ B-CLL cells were labeled with anti-IFN-gamma monoclonal antibodies. These results show that IFN-gamma inhibits programmed cell death in B-CLL cells and suggest that the malignant cells are able to synthesize this cytokine. By delaying apoptosis, IFN-gamma may extend the life span of the malignant cells and thereby contribute to their clonal accumulation.

Ligation of CD38 suppresses human B lymphopoiesis.

CD38 is a transmembrane glycoprotein expressed in many cell types, including lymphoid progenitors and activated lymphocytes. High levels of CD38 expression on immature lymphoid cells suggest its role in the regulation of cell growth and differentiation, but there is no evidence demonstrating a functional activity of CD38 on these cells. We used stroma-supported cultures of B cell progenitors and anti-CD38 monoclonal antibodies (T16 and IB4) to study CD38 function. In cultures of normal bone marrow CD19+ cells (n = 5), addition of anti-CD38 markedly reduced the number of cells recovered after 7 d. Cell loss was greatest among CD19+ sIg- B cell progenitors (mean cell recovery +/- SD = 7.2 +/- 11.7% of recovery in control cultures) and extended to CD19+CD34+ B cells (the most immature subset; 7.6 +/- 2.2%). In contrast, CD38 ligation did not substantially affect cell numbers in cultures of normal peripheral blood or tonsillar B cells. In stroma-supported cultures of 22 B-lineage acute lymphoblastic leukemia cases, anti-CD38 suppressed recovery of CD19+ sIg- leukemic cells. CD38 ligation also suppressed the growth of immature lymphoid cell lines cultured on stroma and, in some cases, in the presence of stroma-derived cytokines (interleukin [IL] 7, IL-3, and/or stem cell factor), but did not inhibit growth in stroma- or cytokine-free cultures. DNA content and DNA fragmentation studies showed that CD38 ligation of stroma-supported cells resulted in both inhibition of DNA synthesis and induction of apoptosis. It is known that CD38 catalyzes nicotinamide adenine dinucleotide (NAD+) hydrolysis into cyclic ADP-ribose (cADPR) and ADPR. However, no changes in NAD+ hydrolysis or cADPR and ADPR production after CD38 ligation were found by high-performance liquid chromatography; addition of NAD+, ADPR, or cADPR to cultures of lymphoid progenitors did not offset the inhibitory effects of anti-CD38. Thus, anti-CD38 does not suppress B lymphopoiesis by altering the enzymatic function of the molecule. In conclusion, these data show that CD38 ligation inhibits the growth of immature B lymphoid cells in the bone marrow microenvironment, and suggest that CD38 interaction with a putative ligand represents a novel regulatory mechanism of B lymphopoiesis.

Mutations in the human lambda5/14.1 gene result in B cell deficiency and agammaglobulinemia.

B cell precursors transiently express a pre-B cell receptor complex consisting of a rearranged mu heavy chain, a surrogate light chain composed of lambda5/14.1 and VpreB, and the immunoglobulin (Ig)-associated signal transducing chains, Igalpha and Igbeta. Mutations in the mu heavy chain are associated with a complete failure of B cell development in both humans and mice, whereas mutations in murine lambda5 result in a leaky phenotype with detectable humoral responses. In evaluating patients with agammaglobulinemia and markedly reduced numbers of B cells, we identified a boy with mutations on both alleles of the gene for lambda5/14.1. The maternal allele carried a premature stop codon in the first exon of lambda5/14.1 and the paternal allele demonstrated three basepair substitutions in a 33-basepair sequence in exon 3. The three substitutions correspond to the sequence in the lambda5/14. 1 pseudogene 16.1 and result in an amino acid substitution at an invariant proline. When expressed in COS cells, the allele carrying the pseudogene sequence resulted in defective folding and secretion of mutant lambda5/14.1. These findings indicate that expression of the functional lambda5/14.1 is critical for B cell development in the human.

PAMELA results on the cosmic-ray antiproton flux from 60 MeV to 180 GeV in kinetic energy.

The satellite-borne experiment PAMELA has been used to make a new measurement of the cosmic-ray antiproton flux and the antiproton-to-proton flux ratio which extends previously published measurements down to 60 MeV and up to 180 GeV in kinetic energy. During 850 days of data acquisition approximately 1500 antiprotons were observed. The measurements are consistent with purely secondary production of antiprotons in the Galaxy. More precise secondary production models are required for a complete interpretation of the results.