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Mars is known to host large quantities of water in solid or gaseous form, and surface rocks show clear evidence that there was liquid water on the planet in the distant past. Whether any liquid water remains on Mars today has long been debated. Orosei et al. used radar measurements from the Mars Express spacecraft to search for liquid water in Mars' southern ice cap (see the Perspective by Diez). They detected a 20-km-wide lake of liquid water underneath solid ice in the Planum Australe region. The water is probably kept from freezing by dissolved salts and the pressure of the ice above. The presence of liquid water on Mars has implications for astrobiology and future human exploration. Science , this issue p. 490 ; see also p. 448 Radar data from Mars Express show that there is a lake of liquid water underneath the solid ice of Mars’ southern ice cap. The presence of liquid water at the base of the martian polar caps has long been suspected but not observed. We surveyed the Planum Australe region using the MARSIS (Mars Advanced Radar for Subsurface and Ionosphere Sounding) instrument, a low-frequency radar on the Mars Express spacecraft. Radar profiles collected between May 2012 and December 2015 contain evidence of liquid water trapped below the ice of the South Polar Layered Deposits. Anomalously bright subsurface reflections are evident within a well-defined, 20-kilometer-wide zone centered at 193°E, 81°S, which is surrounded by much less reflective areas. Quantitative analysis of the radar signals shows that this bright feature has high relative dielectric permittivity (>15), matching that of water-bearing materials. We interpret this feature as a stable body of liquid water on Mars.

Biologics developers are moving beyond antibodies for delivery of a wide range of therapeutic interventions. These non-antibody modalities are often based on ‘natural’ protein scaffolds that are modified to deliver bioactive sequences. Both human-derived and non-human-sourced scaffold proteins have been developed. New types of “non-antibody” scaffolds are still being discovered, as they offer attractive alternatives to monoclonals due to their smaller size, improved stability, and ease of synthesis. They are believed to have low immunogenic potential. However, while several human-sourced protein scaffolds have not been immunogenic in clinical studies, this may not predict their overall performance in other therapeutic applications. A preliminary evaluation of their potential for immunogenicity is warranted. Immunogenicity risk potential has been clearly linked to the presence of T “helper” epitopes in the sequence of biologic therapeutics. In addition, tolerogenic epitopes are present in some human proteins and may decrease their immunogenic potential. While the detailed sequences of many non-antibody scaffold therapeutic candidates remain unpublished, their backbone sequences are available for review and analysis. We assessed 12 example non-antibody scaffold backbone sequences using our epitope-mapping tools (EpiMatrix) for this perspective. Based on EpiMatrix scoring, their HLA DRB1-restricted T cell epitope content appears to be lower than the average protein, and sequences that may act as tolerogenic epitopes are present in selected human-derived scaffolds. Assessing the potential immunogenicity of scaffold proteins regarding self and non-self T cell epitopes may be of use for drug developers and clinicians, as these exciting new non-antibody molecules begin to emerge from the preclinical pipeline into clinical use.

Teriparatide is one of several generic peptides named in a recent Food and Drug Administration (FDA) guidance (FDA-2017-D-5767-0002), which outlines a potential strategy to inform immunogenicity risk assessment for synthetic generic peptides without requiring clinical studies. Specifically, the guidance states that for abbreviated new drug applications (ANDAs), once the sameness of the active pharmaceutical ingredient (API) between the generic product and the reference listed drug is established, developers can mitigate the residual risk of unwanted immunogenicity response by using and tools to characterize differences in product- and process-related impurities between the reference and generic drug products. Regarding product-related impurities, a stated concern is that sequence modifications may create new T-cell epitopes capable of driving unwanted immune responses. Specifically, the guidance sets limits for the relative abundance of each impurity and requests that any new impurity above a certain concentration threshold be evaluated for potential T-cell-driven immunogenicity using orthogonal methods that assess both human leukocyte antigen (HLA) binding and the capacity to elicit a T-cell response. One such orthogonal immunogenicity risk assessment approach was applied to teriparatide (TPT) and several theoretical or observed product-related impurities in the case study described here. First, the immunogenic potential of TPT and selected impurities was assessed using three tools: EpiMatrix, ClustiMer, and JanusMatrix. Second, an method was used to evaluate the binding affinity of TPT and the selected TPT impurities to different class II HLA-DRs . Third, a human peripheral blood mononuclear cell (PBMC) T-cell assay compared T-cell proliferation in response to individual impurities or the reference teriparatide drug product, Forteo , . The orthogonal approaches identified multiple impurities as more immunogenic than TPT. In a novel finding, the analysis revealed a potentially tolerogenic sequence in TPT, which correlated with lower-than-expected immune responses to TPT . The analysis and methods described in this case study may help assess the relative risk of impurities and help identify those with the potential to increase the immunogenicity risk of a generic peptide.

Advances in synthetic peptide synthesis have enabled rapid and cost-effective peptide drug manufacturing. For this reason, peptide drugs that were first produced using recombinant DNA (rDNA) technology are now being produced using solid- and liquid-phase peptide synthesis. While peptide synthesis has some advantages over rDNA expression methods, new peptide-related impurities that differ from the active pharmaceutical ingredient (API) may be generated during synthesis. These impurity byproducts of the original peptide sequence feature amino acid insertions, deletions, and side-chain modifications that may alter the immunogenicity risk profile of the drug product. Impurities resulting from synthesis have become the special focus of regulatory review and approval for human use, as outlined in the FDA’s Center for Drug Evaluation and Research guidance document, “ANDAs for Certain Highly Purified Synthetic Peptide Drug Products That Refer to Listed Drugs of rDNA Origin,” published in 2021. This case study illustrates how in silico and in vitro methods can be applied to assess the immunogenicity risk of impurities that may be present in synthetic generic versions of the salmon calcitonin (SCT) drug product. Sponsors of generic drug abbreviated new drug applications (ANDAs) should consider careful control of these impurities (for example, keeping the concentration of the immunogenic impurities below the cut-off recommended by FDA regulators). Twenty example SCT impurities were analyzed using in silico tools and assessed as having slightly more or less immunogenic risk potential relative to the SCT API peptide. Class II human leukocyte antigen (HLA)-binding assays provided independent confirmation that a 9-mer sequence present in the C-terminus of SCT binds promiscuously to multiple HLA DR alleles, while T-cell assays confirmed the expected T-cell responses to SCT and selected impurities. In silico analysis combined with in vitro assays that directly compare the API to each individual impurity peptide may be a useful approach for assessing the potential immunogenic risk posed by peptide impurities that are present in generic drug products.

Gestational Trophoblastic Disease (GTD) comprises a group of disorders that derive from the placenta. Even if full recovery is generally expected, women diagnosed with GTD have to confront: the loss of a pregnancy, a potentially life-threatening diagnosis and delays in future pregnancies. The aim of the study is to evaluate the psychological impact of GTD, focusing on perceived fertility, depression and anxiety. 37 patients treated for GTD at San Raffaele Hospital, Milan, took part in the study. The STAI-Y (State-Trait Anxiety Inventory), the BDI-SF (Beck Depression Scale-Short Form) and the FPI (Fertility Problem Inventory) were used. Patients were grouped on the basis of presence of children (with or without), age (< or ≥35) and type of diagnosis (Hydatidiform Mole, HM, or Gestational Trophoblastic Neoplasia, GTN). Differences in the values between variables were assessed by a t-type test statistic. Three-way ANOVAs were also carried out considering the same block factors. The study highlights that women suffering from GTN had higher depression scores compared to women suffering from HM. A significant correlation was found between anxiety (state and trait) and depression. Younger women presented higher Global Stress scores on the FPI, especially tied to Need for Parenthood and Relationship Concern subscales. Need for Parenthood mean scores significantly varied between women with and without children too. We can conclude that fertility perception seems to be negatively affected by GTD diagnosis, particularly in younger women and in those without children. Patients should be followed by a multidisciplinary team so as to be supported in the disease's psychological aspects too.

Gestational Trophoblastic Disease comprises a group of benign and malignant disorders that derive from the placenta. Using Leventhal's Common-Sense Model as a theoretical framework, this paper examines illness perception in women who have been diagnosed with this disease. Thirty-one women diagnosed with Gestational Trophoblastic Disease in a hospital in Italy were asked to complete the Illness Perception Questionnaire-Revised to measure the following: illness Identity, illness opinions and causes of Gestational Trophoblastic Disease. High mean scores were observed in the Emotional representations and Treatment control subscales. A significant difference emerged between hydatidiform mole patients and those with gestational trophoblastic neoplasia on the Identity subscale. A significant correlation emerged between \"time since diagnosis\" and the Treatment control subscale. This study is the first to investigate illness perception in Gestational Trophoblastic Disease. From a clinical perspective the results highlight the need for multidisciplinary support programs to promote a more realistic illness perception.

Advances in cancer treatment allow women to be cured and live longer. However, the necessary chemotherapy and radiotherapy regimens have a negative impact on future fertility. Oncofertility has emerged as a new interdisciplinary field to address the issue of gonadotoxicity associated with cancer treatment and to facilitate fertility preservation, including oocyte and ovarian tissue cryopreservation. These fertility issues are often inadequately addressed, and referral rates to oncofertility centers are low. The aim of this study was to report the 3‐year experience of the San Raffaele Oncofertility Unit. A total of 96 patients were referred to the Oncofertility Unit for evaluation after the diagnosis of cancer and before gonadotoxic treatment between April 2011 and June 2014. Of the 96 patients, 30 (31.2%) were affected by breast cancers, 20 (20.8%) by sarcomas, 28 (29.2%) by hematologic malignancies, 13 (13.5%) by central nervous system cancers, 3 (3.1%) by bowel tumors, 1 (1.0%) by Wilms’ tumor, and 1 (1.0%) by a thyroid tumor; 47 (49.0%) were referred for oocyte cryopreservation before starting chemotherapy, 20 (20.8%) were referred for ovarian tissue cryopreservation, and 29 (30.2%) were not recruited. The mean time between the patients’ counseling and oocyte retrieval was 15 days (range, 2–37 days). The mean time between the laparoscopic surgery and the beginning of treatment was 4 days (range, 2–10 days). The number of patients who were referred increased over time, whereas the rate of patients who were not recruited decreased, showing an improvement in referrals to the Oncofertility Unit and in the patients’ counseling and understanding. Our results indicate that an effective multidisciplinary oncofertility team is necessary for prompt referrals and treatment.

Current debates on austerity often forget that these policies are almost a hundred years old. This article explores how the combination of austerity and technocracy acted as a powerful tool to secure the compliance of European countries with socio-economic stabilization after the First World War. Austerity emerged as an economic, moral, and technocratic message as economic experts sought to educate restless post-war civil society. The article analyses primary austerity documents from the international economic conferences of Brussels (1920) and Genoa (1922). In addition, I use a case study of Italy (1922-1925) to show how austerity succeeded under the first years of Fascism, when the government authorized prominent economics professors to implement the international financial codes devised at Brussels and Genoa. I also consider the scientific writings of De Stefani, Ricci, and Pantaleoni in order to examine the theoretical roots of the technocratic nature of austerity.

Objective Previous studies have shown that taking care of elderly, demented patients carries a high cost to caregivers’ health, and is associated with negative consequences for physical and mental health. The aim of this study is to investigate which socio-demographic and clinical variables are significantly associated with higher levels of distress in caregivers, and the relationship between caregivers’ levels of distress and the coping strategies they adopt. Patients and participants The study samples 112 caregivers of demented patients, consecutively admitted to the Department of Neurology of San Raffaele-Turro Hospital (Milan, Italy). Measurements and results Caregivers were asked to complete the CBI and the COPE. Caregivers with the highest levels of distress are characterised by an impaired physical health status. Avoidance coping may represent a risk factor associated with higher levels of distress; conversely, an active and problem-focused approach to stressful situations may act as a protective factor.

The tumor suppressor p53 is mainly involved in the transcriptional regulation of a large number of growth-arrest- and apoptosis-related genes. However, a clear understanding of which factor/s influences the choice between these two opposing p53-dependent outcomes remains largely elusive. We have previously described that in response to DNA damage, the RNA polymerase II-binding protein Che-1/AATF transcriptionally activates p53. Here, we show that Che-1 binds directly to p53. This interaction essentially occurs in the first hours of DNA damage, whereas it is lost when cells undergo apoptosis in response to posttranscriptional modifications. Moreover, Che-1 sits in a ternary complex with p53 and the oncosuppressor Brca1. Accordingly, our analysis of genome-wide chromatin occupancy by p53 revealed that p53/Che1 interaction results in preferential transactivation of growth arrest p53 target genes over its pro-apoptotic target genes. Notably, exposure of Che-1 +/− mice to ionizing radiations resulted in enhanced apoptosis of thymocytes, compared with WT mice. These results confirm Che-1 as an important regulator of p53 activity and suggest Che-1 to be a promising yet attractive drug target for cancer therapy.