Unlocking the Potential: Caloric Restriction, Caloric Restriction Mimetics, and Their Impact on Cancer Prevention and Treatment.

Caloric restriction (CR) and its related alternatives have been shown to be the only interventions capable of extending lifespan and decreasing the risk of cancer, along with a reduction in burden in pre-clinical trials. Nevertheless, the results from clinical trials have not been as conclusive as the pre-clinical results. Recognizing the challenges associated with long-term fasting, the application of caloric restriction mimetics (CRMs), pharmacological agents that mimic the molecular effects of CR, to harness the potential benefits while overcoming the practical limitations of fasting has resulted in an interesting alternative. This review synthesizes the findings of diverse clinical trials evaluating the safety and efficacy of CR and CRMs. In dietary interventions, a fast-mimicking diet was the most tolerated to reduce tumoral growth markers and chemotherapy side effects. CRMs were well tolerated, and metformin and aspirin showed the most promising effect in reducing cancer risk in a selected group of patients. The application of CR and/or CRMs shows promising effects in anti-cancer therapy; however, there is a need for more evidence to safely include these interventions in standard-of-care therapies.

Dual First and Second Surface Solar Mirrors of Polished WS2 and Silver by Dynamical Chemical Plating Technique on Polycarbonate.

This work proposes for the first time protecting-reflecting on both sides of plated mirrors and a solution to polycarbonate surface vulnerability to weathering and scratching using tungsten disulfide (WS2) by mechanical polishing. The ability of the dynamic chemical plating (DCP) technique to deposit Ag films at the nanometer scale on a polycarbonate (PC) substrate and its characteristics to be metallized is also shown. These deposits hold significant promise for concentrated solar power (CSP) applications. Complementarily, the application of WS2 as a reflective film for CSP by mechanical polishing on smooth polycarbonate surfaces is both novel and practical. This technique is innovative and scalable without needing reactants or electrical potential, making it highly applicable in real-world scenarios, including, potentially, on-site maintenance. The effects of surface morphology and adhesion, and the reflectivity parameters of the silver metallic surfaces were investigated. Wettability was investigated because it is important for polymeric surfaces in the activation and metal deposition immediately after redox reactions. The flame technique improved wettability by modifying the surface with carbonyl and carboxyl functional groups, with PC among the few industrial polymers that resisted such a part of the process. The change in the chemical composition, roughness, and wettability of the surfaces effectively improved the adhesion between the Ag film and the PC substrate. However, it did not significantly affect the adhesion between PC and WS2 and showed its possible implementation as a first surface mirror. Overall, this work provides a scalable, innovative method for improving the durability and reflectivity of polycarbonate-based mirrors, with significant implications for CSP applications.

First-attempt awake tracheal intubation success rate using a hyperangulated unchannelled videolaryngoscope vs. a channelled videolaryngoscope in patients with anticipated difficult airway: a randomised controlled trial.

INTRODUCTION: There is uncertainty about the optimal videolaryngoscope for awake tracheal intubation in patients with anticipated difficult airway. The use of channelled and unchannelled videolaryngoscopy has been reported, but there is a lack of evidence on which is the best option. METHODS: We conducted a randomised clinical trial to compare the efficacy of the C-MAC D-Blade® vs. Airtraq® in adult patients (aged ≥ 18 y) scheduled for elective or emergency surgery under general anaesthesia with anticipated difficult airway who required awake tracheal intubation under local anaesthesia and conscious sedation. The primary endpoint was the first-attempt tracheal intubation success rate. Secondary outcomes included the overall success rate; number of tracheal intubation attempts; Cormack and Lehane glottic view; level of difficulty (visual analogue score); patient discomfort (visual analogue score); and incidence of complications. RESULTS: Ninety patients (70/90 male (78%); mean (SD) age 65 (12) y) with anticipated difficult airways were randomly allocated to C-MAC D-Blade or Airtraq videolaryngoscopy. First-attempt successful tracheal intubation rate was higher in patients allocated to the C-MAC D-Blade group compared with those allocated to the Airtraq group (38/45 (84%) vs. 28/45 (62%), respectively; p = 0.006). The proportion of patients' tracheas that were intubated at the second and third attempt was 4/45 (9%) and 3/45 (7%) in those allocated to the C-MAC D-Blade group compared with 14/45 (31%) and 1/45 (2%) in those allocated to the Airtraq group (p = 0.006). There was no significant difference in overall tracheal intubation success rate (C-MAC D-Blade group 45/45 (100%) vs. Airtraq group 43/45 (96%), p = 0.494). DISCUSSION: In patients with anticipated difficult airway, first-attempt awake tracheal intubation success rate was higher with the C-MAC D-Blade compared with Airtraq laryngoscopy. No difference was found between the two videolaryngoscopes in overall tracheal intubation success rate.

Analysis of T follicular and T peripheral helper lymphocytes in autoimmune thyroid disease.

PURPOSE: Peripheral helper T (Tph) cells have an important role in the induction of humoral immune responses and autoantibody production. Accordingly, it is feasible that this lymphocyte subset has a relevant role in the pathogenesis of autoimmune thyroid diseases (AITD). In this study we aim to analyze the levels and function of Tph cells in blood samples from patients with AITD. METHODS: We performed an observational study with cases and controls. Blood samples were obtained from nineteen patients with Hashimoto's thyroiditis (HT), twenty-four with Graves' disease (GD), and fifteen healthy controls. In addition, the levels of follicular T helper (Tfh) cells and Tph cells, the release of interleukin-21 (IL-21) by these lymphocytes and the number of plasmablasts were analyzed by multi-parametric flow cytometry analyses. RESULTS: Increased percentages of Tfh and Tph lymphocytes were detected in patients with HT and GD. Furthermore, an enhanced synthesis of the cytokine IL-21 by these cells was observed. Accordingly, we detected significant higher percentages of plasmablasts in patients with GD, and these values tended to be also higher in HT patients. Moreover, significant positive associations were observed between the levels of Tfh or Tph and the number of plasmablast or anti-TSHR Ab titers in patients with AITD. CONCLUSION: Our data suggest that Tph lymphocytes may have a relevant role in the pathogenesis of AITD.

A Randomized Clinical Trial to Evaluate the Efficacy of an Oral Probiotic in Acne Vulgaris.

The relevance of the gut microbiota in some skin inflammatory diseases, including acne vulgaris, has been emphasized. Probiotics could play a role in the modulation of the microbiota, improving the clinical course of this disease. A 12-week randomized, double-blind, placebo-controlled, clinical trial with patients aged 12 to 30 years with acne vulgaris was conducted. The study product was a capsule composed of the probiotic Lacticaseibacillus rhamnosus (CECT 30031) and the cyanobacterium Arthrospira platensis (BEA_IDA_0074B). Patients with improvement in the Acne Global Severity Scale were 10/34 (29.41%) in the placebo group compared with 20/40 (50%) in the probiotic group (p = 0.03). A significant reduction (p = 0.03) in the number of non-inflammatory acne lesions was observed in the probiotic group (-18.60 [-24.38 to -12.82]) vs the placebo group (-10.54 [-17.43 to -3.66]). Regarding the number of total  lesions, a reduction almost reaching statistical significance (p = 0.06) was observed in the probiotic group (-27.94 [-36.35 to -19.53]) compared with the placebo group (-18.31 [-28.21 to -8.41]). In addition, patients with improvement attending the Global Acne Grading System were 7/34 (20.58%) in the placebo group vs 17/40 (42.50%) in the probiotic group (p = 0.02). The number of adverse events was similar in both groups. The probiotic used in this study was effective and well tolerated, and it should be considered for acne vulgaris patients.

Effects of lethal management on gray wolf pack persistence and reproduction in Wisconsin, USA.

Direct human-caused mortality accounts for about half of all large mammal mortality in North America. For social species like gray wolves (Canis lupus), the death of pack members can disrupt pack structure and cause pack dissolution, and mortality of breeding adults or wolves during reproduction and pup-rearing can decrease pup recruitment. We estimated minimum and maximum probability of wolf pack persistence in Wisconsin, USA, during biological years (15 April-14 April) 2011-2019 and evaluated the influence of pack size and legal harvest mortality on pack persistence during 2012-2014. Harvests comprised 75-161 mortalities within 194 monitored packs during 2012-2014, with 56-74% of packs having no wolves harvested each year. As an index of reproduction during 2013-2019, we also estimated the proportion of packs where pups responded to howl surveys. We evaluated the influence of pack size, legal harvest, and agency removal on reproduction during 2013-2015. Annual maximum pack persistence probability was uniformly high (0.95-1.00), and annual minimum pack persistence probability ranged from 0.86-0.98 with a possible decline during years of harvest. Reproduction was similar in years following harvest and agency removal (2013-2015, pup response = 0.27-0.40), and years without harvest or agency removal the year prior (2016-2019, pup response = 0.28-0.66). Pack size had a positive effect on pack persistence and reproduction. Total number of wolf mortalities and number of adult male and females removed did not influence pack persistence or reproduction. We suggest that low per-pack mortality, timing of harvest and agency removal, and harvest characteristics during 2012-2014 supported stable pack persistence and reproduction.

Polymer Waste Recycling of Injection Molding Purges with Softening for Cutting with Fresnel Solar Collector-A Real Problem Linked to Sustainability and the Circular Economy.

A plastic injection waste known as "purge" cannot be reintegrated into the recycling chain due to its shape, size, and composition. Grinding these cannot be carried out with traditional mills due to significant variations in size and shape. This work proposes a process and the design of a device that operates with solar energy to cut the purges without exceeding the degradation temperature. The size reduction allows reprocessing, revalorization, and handling. The purges are mixtures of processed polymers, so their characterization information is unavailable. Some characterizations were conducted before the design of the process and after the cut of the purges. Some of the most representative purges in a recycling company were evaluated. The flame test determines that all material mixtures retain thermoplasticity. The hardness (Shore D) presented changes in four of the purges being assessed, with results in a range of 59-71 before softening and 60-68 after softening. Young's modulus was analyzed by the impulse excitation technique (IET), which was 2.38-3.95 GPa before softening and 1.7-4.28 after softening. The feasibility of cutting purges at their softening temperature was evaluated. This was achieved in all the purges evaluated at 250-280 °C. FTIR allowed for corroboration of no significant change in the purges after softening. The five types of purges evaluated were polypropylene-ABS, polycarbonate-ABS-polypropylene, yellow nylon 66, acetal, and black nylon 66 with fillers, and all were easily cut at their softening temperature, allowing their manipulation in subsequent process steps.

Long-term antigen-specific immune response by an oncolytic adenovirus encoding SP-SA-E7-4-1BBL in HPV-16 cancer model.

BACKGROUND: To describe an oncolytic adenovirus (OAd) encoding SP-SA-E7-4-1BBL that is capable of inducing tumor regression in therapeutic assays. Herein, we tested whether the antitumor effect is given by the induction of a tumor-specific immune response, as well as the minimum dose needed to elicit antitumor protection and monitor the OAd biodistribution over time. METHODS AND RESULTS: C57BL/6 mice (n = 5) per group were immunized twice with OAds encoding SP-SA-E7-4-1BBL, SA-E7-4-1BBL, or SP-SA-4-1BBL and challenged with TC-1 cancer cells. The DNA construct SP-SA-E7-4-1BBL was employed as a control via biolistic or PBS injection. Groups without tumor development at 47 days were rechallenged with TC-1 cells, and follow-up lasted until day 90. The minimum dose of OAd to induce the antitumor effect was established by immunization using serial dilution doses. The cytometry bead assay and the ELISpot assay were used to evaluate cytokine release in response to ex vivo antigenic stimulation. The distribution profile of the OAd vaccine was evaluated in the different organs by histological, immunohistochemical and qPCR analyses. The OAd SP-SA-E7-4-1BBL-immunized mice did not develop tumors even in a rechallenge. A protective antitumor effect was observed from a dose that is one hundredth of most reports of adenoviral vaccines. Immunization with OAd increases Interferon-gamma-producing cells in response to antigen stimulation. OAd was detected in tumors over time, with significant morphological changes, contrary to nontumor tissues. CONCLUSIONS: The OAd SP-SA-E7-4-1BBL vaccine confers a prophylactic, safe, long-lasting, and antigen-dependent antitumor effect mediated by a Th1 antitumor immune response.

Impact of COVID-19 on Perinatal Outcomes and Birth Locations in a Large US Metropolitan Area.

This was a population-based study to determine the impact of COVID-19 on birth outcomes in the Chicago metropolitan area, comparing pre-pandemic (April-September 2019) versus pandemic (April-September 2020) births. Multivariable regression models that adjusted for demographic and neighborhood characteristics were used to estimate the marginal effects of COVID-19 on intrauterine fetal demise (IUFD)/stillbirth, preterm birth, birth hospital designation, and maternal and infant hospital length of stay (LOS). There were no differences in IUFD/stillbirths or preterm births between eras. Commercially insured preterm and term infants were 4.8 percentage points (2.3, 7.4) and 3.4 percentage points (2.5, 4.2) more likely to be born in an academic medical center during the pandemic, while Medicaid-insured preterm and term infants were 3.6 percentage points less likely (-6.5, -0.7) and 1.8 percentage points less likely (-2.8, -0.9) to be born in an academic medical center compared to the pre-pandemic era. Infant LOS decreased from 2.4 to 2.2 days (-0.35, -0.20), maternal LOS for indicated PTBs decreased from 5.6 to 5.0 days (-0.94, -0.19), and term births decreased from 2.5 to 2.3 days (-0.21, -0.17). The pandemic had a significant effect on the location of births that may have exacerbated health inequities that continue into childhood.

Genomics, Transcriptomics, and Epigenetics of Sporadic Pituitary Tumors.

Pituitary tumors (PT) are highly heterogeneous neoplasms, comprising functioning and nonfunctioning lesions. Functioning PT include prolactinomas, causing amenorrhea-galactorrhea in women and sexual dysfunction in men; GH-secreting adenomas causing acromegaly-gigantism; ACTH-secreting corticotrophinomas causing Cushing disease (CD); and the rare TSH-secreting thyrotrophinomas that result in central hyperthyroidism. Nonfunctioning PT do not result in a hormonal hypersecretion syndrome and most of them are of gonadotrope differentiation; other non-functioning PT include null cell adenomas and silent ACTH-, GH- and PRL-adenomas. Less than 5% of PT occur in a familial or syndromic context whereby germline mutations of specific genes account for their molecular pathogenesis. In contrast, the more common sporadic PT do not result from a single molecular abnormality but rather emerge from several oncogenic events that culminate in an increased proliferation of pituitary cells, and in the case of functioning tumors, in a non-regulated hormonal hypersecretion. In recent years, important advances in the understanding of the molecular pathogenesis of PT have been made, including the genomic, transcriptomic, epigenetic, and proteomic characterization of these neoplasms. In this review, we summarize the available molecular information pertaining the oncogenesis of PT.

Mouse and human studies support DSTYK loss of function as a low-penetrance and variable expressivity risk factor for congenital urinary tract anomalies.

PURPOSE: Previous work identified rare variants in DSTYK associated with human congenital anomalies of the kidney and urinary tract (CAKUT). Here, we present a series of mouse and human studies to clarify the association, penetrance, and expressivity of DSTYK variants. METHODS: We phenotypically characterized Dstyk knockout mice of 3 separate inbred backgrounds and re-analyzed the original family segregating the DSTYK c.654+1G>A splice-site variant (referred to as "SSV" below). DSTYK loss of function (LOF) and SSVs were annotated in individuals with CAKUT, epilepsy, or amyotrophic lateral sclerosis vs controls. A phenome-wide association study analysis was also performed using United Kingdom Biobank (UKBB) data. RESULTS: Results demonstrate ∼20% to 25% penetrance of obstructive uropathy, at least, in C57BL/6J and FVB/NJ Dstyk-/- mice. Phenotypic penetrance increased to ∼40% in C3H/HeJ mutants, with mild-to-moderate severity. Re-analysis of the original family segregating the rare SSV showed low penetrance (43.8%) and no alternative genetic causes for CAKUT. LOF DSTYK variants burden showed significant excess for CAKUT and epilepsy vs controls and an exploratory phenome-wide association study supported association with neurological disorders. CONCLUSION: These data support causality for DSTYK LOF variants and highlights the need for large-scale sequencing studies (here >200,000 cases) to accurately assess causality for genes and variants to lowly penetrant traits with common population prevalence.

Beyond the anti-PD-1/PD-L1 era: promising role of the BTLA/HVEM axis as a future target for cancer immunotherapy.

Recent introduction of monoclonal antibodies targeting immune checkpoints to harness antitumor immunity has revolutionized the cancer treatment landscape. The therapeutic success of immune checkpoint blockade (ICB)-based therapies mainly relies on PD-1/PD-L1 and CTLA-4 blockade. However, the limited overall responses and lack of reliable predictive biomarkers of patient´s response are major pitfalls limiting immunotherapy success. Hence, this reflects the compelling need of unveiling novel targets for immunotherapy that allow to expand the spectrum of ICB-based strategies to achieve optimal therapeutic efficacy and benefit for cancer patients. This review thoroughly dissects current molecular and functional knowledge of BTLA/HVEM axis and the future perspectives to become a target for cancer immunotherapy. BTLA/HVEM dysregulation is commonly found and linked to poor prognosis in solid and hematological malignancies. Moreover, circulating BTLA has been revealed as a blood-based predictive biomarker of immunotherapy response in various cancers. On this basis, BTLA/HVEM axis emerges as a novel promising target for cancer immunotherapy. This prompted rapid development and clinical testing of the anti-BTLA blocking antibody Tifcemalimab/icatolimab as the first BTLA-targeted therapy in various ongoing phase I clinical trials with encouraging results on preliminary efficacy and safety profile as monotherapy and combined with other anti-PD-1/PD-L1 therapies. Nevertheless, it is anticipated that the intricate signaling network constituted by BTLA/HVEM/CD160/LIGHT involved in immune response regulation, tumor development and tumor microenvironment could limit therapeutic success. Therefore, in-depth functional characterization in different cancer settings is highly recommended for adequate design and implementation of BTLA-targeted therapies to guarantee the best clinical outcomes to benefit cancer patients.

On the occasion of the centennial of the Nobel Prize in Physiology or Medicine, 1923: Nicolae C. Paulescu-between scientific creativity and political fanatism.

AIMS: Since the Nobel Prize in Physiology or Medicine was awarded in 1923 to FG Banting and JJR Macleod, many voices have been raised against this decision. The bitterest protest was that of the Romanian scientist Nicolae C. Paulescu. In 2002, The Romanian Academy of Sciences, the European Association for the Study of Diabetes (EASD) and the International Diabetes Federation (IDF) planned to hold a series of academic events the following year in Paris to acknowledge Paulescu's scientific merits in the discovery of the antidiabetic hormone. However, the initiative was cancelled in August 2003, when the European Center of the Simon Wiesenthal Foundation (SWC) accused Paulescu of being antisemitic. The authors of this manuscript have decided to approach "the Paulescu case" from its double aspect, scientific and sociopolitical, to analyze the circumstances surrounding the discovery of the antidiabetic hormone, and Paulescu's alleged antisemitic past in the historical context of the Romanian nation in the interwar period. METHODS: We contacted the SWC and people related to the 2003 events in Paris. We performed a comparative review of the documents published by the Toronto group and by Paulescu and analyzed the correspondence and articles generated by international experts from the scientific community interested in the controversy. We carried out an exhaustive bibliographic search through several online catalogs (INDEXCAT, NLM Gateway, EUREKA, MEDHIST). We travelled to Bucharest, where we visited Paulescu's house-museum, interviewed a former student of the Romanian professor, and a prominent medical historian who was knowledgeable about Paulescu's scientific and political biography. Dan Angelescu†, son of Dr. Constantin Angelescu (1904-1990), Paulescu's nephew and collaborator, provided us with a copy of all the available documentation from Paulescu's personal archive. It constitutes an essential source for understanding Paulescu's personal, political and academic biography. Archives consulted: Românǎ Academy (Bucharest). Personal Archive of Paulescu, House -Museum (Bucharest)*. Romanian Jewish Heritage (Bucharest). http://romanianjewish.org/ **. Simon Wiesenthal Center (Los Angeles, CA) http://www.wiesenthal.com **. Romanian Patent Office. Oficiul de Stat pentru Invenții si Mǎrci (OSIM) (Bucharest)***. Nobel Archives (Stockholm) https://www.nobelprize.org . Internet Archive (San Francisco, CA) https://archive.org **. Wellcome Library (London) https://wellcomelibrary.org **. The European Library https://www.theeuropeanlibrary.org/ **. US National Library of Medicine, NLM historical collections http://www.nlm.nih.gov/hmd/index.html **. US. Holocaust Memorial Museum http://www.ushmm.org/ (*: archive consulted on site; **: material found in the online catalog of the archive; ***: archivists sent us digitized copies of archival material). Books consulted for information on the history of Romania and antisemitism: "Nationalist ideology and antisemitism. The case of Romanian intellectuals in the 1930s", by Leon Volovici; "The mystique of ultranationalism: History of the Iron Guard, Romania, 1919-1941" by Francisco Vega; "Romania 1866-1947", by Keith Hitchins; "History of Romania. Compendium", by Ioan-Aurel Pop and Joan Bolovan; "The Holocaust in Romania. The destruction of Jews and Gypsies under the Antonescu regime, 1940-1944", by Radu Ioanid; "The Jews of East Central Europe between the World Wars", by Ezra Mendelson; "Cultural Politics in Greater Romania. Regionalism, Nation Building and Ethnic Struggle, 1918-1930", by Irina Livezeanu, and "Judeophobia. How and when it is born, where and why it survives", by Gustavo Daniel Perednik. Articles are referenced in the bibliography section at the end of the manuscript. RESULTS: A-Nicolae Paulescu developed an intense long-term research activity, which included complete pancreatectomy and preparation of a pancreatic extract (PE) containing the antidiabetic hormone he called pancreina. Parenteral administration of the PE achieved excellent results in the treatment of experimental diabetes in dogs and induction of hypoglycemia in the healthy animal. This work was initiated before 1916 and published at least eight months antedating the publication of the first article by Banting and Best (February 1922), who were acquainted with Paulescu's results, but misinterpreted them. The pancreatic extract of the two Canadian researchers, -iletin/insulin-, only achieved similar results to that of the Romanian scientist once they abandoned the use of the "degenerated pancreas" extract (ligation of the ductal system), replacing it with the pancreas of adult or fetal bovine. Pancreina and insulin were very similar. The award of the Nobel Prize in Physiology or Medicine to FG Banting and JJR Macleod in October 1923 honored the successful clinical use of insulin in patients with diabetes mellitus. Paulescu's achievements were ignored. B-Nicolae Paulescu publicly manifested his Judeophobic ideology on multiple occasions in academic and political interventions and in publications and participated with other figures from the Romanian intellectual sphere in the founding of the Uniunea Național Crestinǎ (UNC, National Christian Union) in 1922 and of the Liga Apǎrǎrii Național Cresține (LANC, League for Christian National Defense) in 1923, antisemitic far-right political parties, associated with an irrational Christian orthodoxy and hatred of Jews. Paulescu played a pivotal role in the spread of antisemitism. CONCLUSIONS: A-The Romanian scientist NC Paulescu started an intense research program aimed at the isolation of the antidiabetic hormone before 1916, including an original procedure of pancreatectomy in the dog and the elaboration of a pancreatic extract that achieved excellent results in the treatment of experimental diabetes, demonstrating its beneficial effects on the metabolism of carbohydrates, proteins and fats and reducing both glycosuria and glycemia and the urinary excretion of ketone bodies of depancreatized dogs toward normality. The results of these investigations were published in 1920 and 1921, predating the first report published by FG ​​Banting and CH Best in February 1922. It has been sufficiently demonstrated that Canadian researchers were aware of Paulescu's excellent results, mentioning them only in passing, albeit erroneously misrepresenting key results of the Romanian scientist's publication in the aforementioned seminal Canadian article. Expert historians and international scientists have recognized that the pancreatic extract that Paulescu called pancreina and that obtained by Banting and Best, insulin, were very similar. The October 1923 award of the Nobel Prize in Physiology or Medicine to FG Banting and JJR Macleod ignored Paulescu's scientific achievements in the treatment of experimental diabetes and rewarded the extraordinary advance of insulin treatment in human diabetes. B-At the end of August 2003, a few days before the date of the celebration at the Hôtel Dieu in Paris of the scheduled program of tribute to the scientific merits of NC Paulescu and his important contribution to the discovery of the antidiabetic hormone, convened by the Romanian Academy and the International Diabetes Federation, the Wiesenthal Foundation publicly accused the Romanian scientist of being an antisemite, an act that determined the cancellation of the announced events. The exhaustive investigation of the personal convictions and antisemitic behavior of Nicolae C. Paulescu has undoubtedly documented the Judeophobic ideology of the Romanian scientist, linked to his orthodox religious radicalism, manifested in multiple documents (mostly pamphlets) and interventions in collaboration with other relevant personalities of the Romanian intelligentsia of his time. Furthermore, Paulescu participated in the creation of political organizations of the most radical extreme right that played a fundamental role in the spread of antisemitism amongst the Romanian population and the university community.

The Nobel Prize of Physiology or Medicine, 1923: controversies on the discovery of the antidiabetic hormone.

AIMS: To analyze the main contributions to the discovery of the antidiabetic hormone in the period between 1889, the year in which Oskar Minkowski demonstrated that complete pancreatectomy in dogs caused diabetes, and the year 1923, the date in which the clinical use of insulin was consolidated. A main objective has been to review the controversies that followed the Nobel Prize and to outline the role of the priority rule in Science. METHODS: We have considered the priority rule defined by Robert Merton in 1957, which takes into account the date of acceptance of the report of a discovery in an accredited scientific journal and/or the granting of a patent, complemented by the criteria set out by Ronald Vale and Anthony Hyman (2016) regarding the transfer of information to the scientific community and its validation by it. The awarding of the Nobel Prize in Physiology or Medicine in October 1923 has represented a frame of reference. The claims and disputes regarding the prioritization of the contributions of the main researchers in the organotherapy of diabetes have been analyzed through the study of their scientific production and the debate generated in academic institutions. MAIN RESULTS AND CONCLUSIONS: (1) According to the criteria of Merton, Vale and Hyman, the priority of the discovery of the antidiabetic hormone corresponds to the investigations developed in Europe by E. Gley (1900), GL Zülzer (1908) and NC Paulescu (1920). (2) The active principle of the pancreatic extracts developed by Zülzer (acomatol), Paulescu (pancreina) and Banting and Best (insulin) was the same. (3) JB Collip succeeded in isolating the active ingredient from the pancreatic extract in January 1922, eliminating impurities to the point of enabling its use in the clinic. (4) In 1972, the Nobel Foundation modified the purpose of the 1923 Physiology or Medicine award to Banting and Macleod by introducing a new wording: "the credit for having produced the pancreatic hormone in a practical available form" (instead of "for the discovery of insulin").

Chemo-Immunotherapy: A New Trend in Cancer Treatment.

Chemotherapy has been the basis of advanced cancer treatment for decades. This therapy has largely been considered immunosuppressive, yet accumulated preclinical and clinical evidence shows that certain chemotherapeutic drugs, under defined conditions, may stimulate antitumor immunity and potentiate immune checkpoint inhibitor (ICI)-based therapy. Its effectiveness has been highlighted by recent regulatory approvals of various combinations of chemotherapy with ICIs in several tumors, particularly in some difficult-to-treat cancers. This review discusses the immune modulatory properties of chemotherapy and how they may be harnessed to develop novel chemo-immunotherapy combinations. It also highlights the key determinants of the success of chemo-immunotherapy and provides an overview of the combined chemo-immunotherapies that have been clinically approved.

Evolution of laboratory parameters in patients with lipid transfer protein syndrome after 3 years of immunotherapy

Lipid transfer protein (LTP) syndrome is an increasingly prevailing disease, especially in the young population, with severely affected quality of life. Since 2013, a specific treatment, called sublingual immunotherapy (SLIT), with peach extract (SLIT-peach®) has been used, but with no long-term effectiveness studies. The main objective of the present study was to assess the long-term effectiveness of SLIT-peach® and to relate the clinical evolution of patients. This was an ambispective study conducted for 3 years. A total of 25 patients with LTP syndrome were selected and treated with SLIT-peach®. They underwent a provocation test in the first year with reintroduced foods that had produced symptoms in the past. Analytical determination of specific immunoglobulin E (IgE) and immunoglobulin G4 (IgG4) to peach (Pru p 3) was performed at the beginning of treatment, at the first year of initiation, and at the end of treatment. These data were compared with the control group comprising 14 patients with LTP syndrome without treatment. A statistically significant decrease in specific IgE to Pru p 3 at the end of the treatment and an increase in specific IgG4 to Pru p 3 1 year after treatment initiation were observed in the active group in relation to tolerance to foods with LTPs. These results indicate that food tolerance begins after the first year and is maintained after the end of 3 years of treatment. In conclusion, treatment with SLIT-peach® for 3 years is effective for patients with LTP syndrome, preventing the evolution of the disease, allowing patients to restart a diet with plant foods, and improving their quality of life (AU)

Evolution of laboratory parameters in patients with lipid transfer protein syndrome after 3 years of immunotherapy.

Lipid transfer protein (LTP) syndrome is an increasingly prevailing disease, especially in the young population, with severely affected quality of life. Since 2013, a specific treatment, called sublingual immunotherapy (SLIT), with peach extract (SLIT-peach®) has been used, but with no long-term effectiveness studies. The main objective of the present study was to assess the long-term effectiveness of SLIT-peach® and to relate the clinical evolution of patients. This was an ambispective study conducted for 3 years. A total of 25 patients with LTP syndrome were selected and treated with SLIT-peach®. They underwent a provocation test in the first year with reintroduced foods that had produced symptoms in the past. Analytical determination of specific immunoglobulin E (IgE) and immunoglobulin G4 (IgG4) to peach (Pru p 3) was performed at the beginning of treatment, at the first year of initiation, and at the end of treatment. These data were compared with the control group comprising 14 patients with LTP syndrome without treatment. A statistically significant decrease in specific IgE to Pru p 3 at the end of the treatment and an increase in specific IgG4 to Pru p 3 1 year after treatment initiation were observed in the active group in relation to tolerance to foods with LTPs. These results indicate that food tolerance begins after the first year and is maintained after the end of 3 years of treatment. In conclusion, treatment with SLIT-peach® for 3 years is effective for patients with LTP syndrome, preventing the evolution of the disease, allowing patients to restart a diet with plant foods, and improving their quality of life.