The acceleration of metastases after tumor removal and the paradoxical phenomenon of concomitant tumor resistance

Although surgical extirpation of tumors is usually clinically recommended, tumor removal may entail an undesired side effect: the risk of accelerating the growth of metastases. This effect may account for the relatively modest survival benefits observed when surgery is accomplished after tumor cells have already disseminated to distant anatomical sites even when tumor removal is combined with chemotherapy or immunotherapy. Although different mechanisms could contribute to the enhancement of residual tumor growth after tumor removal, probably a main effect is associated with the withdrawing of an inhibitory effect generated, by certain circumstances, by the primary tumor on its own metastases. This inhibitory effect is a particular case of a more general and paradoxical phenomenon known as concomitant tumor resistance (CR) in which a tumor-bearing host inhibits or retards the growth of secondary tumor implants despite the fact that the primary tumor grows progressively. In this essay we especially focus on the last investigations of our laboratory concerningthe importance of tyrosine isomers as mediators of the phenomenon of CR and on their capacity to inhibit established metastases. Taking into account that metastases are considered the main problem in cancer pathology, our investigations aimed to elucidate the molecular basis of the phenomenon of CR might stimulate the design of new and less harmful means of managing malignant diseases, especially by controlling the growth of metastases after the removal of a primary tumor, or after other injuries or stressors that have been claimed to promote the escape of metastases from dormancy.Fil: Montagna, Daniela Romina. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Medicina Experimental. Academia Nacional de Medicina de Buenos Aires. Instituto de Medicina Experimental; ArgentinaFil: Chiarella, Paula. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Medicina Experimental. Academia Nacional de Medicina de Buenos Aires. Instituto de Medicina Experimental; ArgentinaFil: Meiss, Roberto P.. Academia Nacional de Medicina de Buenos Aires; ArgentinaFil: Ruggiero, Raul Alejandro. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Medicina Experimental. Academia Nacional de Medicina de Buenos Aires. Instituto de Medicina Experimental; Argentin

Improvement of antitumor therapies based on vaccines and immune-checkpoint inhibitors by counteracting tumor-immunostimulationw

Immune-checkpoint inhibitors and antitumor vaccines may produce both tumor-inhibitory and tumor-stimulatory effects on growing tumors depending on the stage of tumor growth at which treatment is initiated. These paradoxical results are not necessarily incompatible with current tumor immunology but they might better be explained assuming the involvement of the phenomenon of tumor immunostimulation. This phenomenon was originally postulated on the basis that the immune response (IR) evoked in Winn tests by strong chemical murine tumors was not linear but biphasic, with strong IR producing inhibition and weak IR inducing stimulation of tumor growth. Herein, we extended those former observations to weak spontaneous murine tumors growing in pre-immunized, immune-competent and immune-depressed mice. Furthermore, we demonstrated that the interaction of specifical T cells and target tumor cells at low stimulatory ratios enhanced the production of chemokines aimed to recruit macrophages at the tumor site, which, upon activation of toll-like receptor 4 and p38 signaling pathways, would recruit and activate more macrophages and other inflammatory cells which would produce growth-stimulating signals leading to an accelerated tumor growth. On this basis, the paradoxical effects achieved by immunological therapies on growing tumors could be explained depending upon where the therapy-induced IR stands on the biphasic IR curve at each stage of tumor growth. At stages where tumor growth was enhanced (medium and large-sized tumors), counteraction of the tumor-immunostimulatory effect with anti-inflammatory strategies or, more efficiently, with selective inhibitors of p38 signaling pathways enabled the otherwise tumor-promoting immunological strategies to produce significant inhibition of tumor growth.Fil: Chiarella, Paula. Academia Nacional de Medicina de Buenos Aires; ArgentinaFil: Vermeulen, Mónica. Academia Nacional de Medicina de Buenos Aires; ArgentinaFil: Montagna, Daniela R.. Academia Nacional de Medicina de Buenos Aires; ArgentinaFil: Vallecorsa, Pablo. Academia Nacional de Medicina de Buenos Aires; ArgentinaFil: Strazza, Ariel Ramiro. Academia Nacional de Medicina de Buenos Aires; ArgentinaFil: Meiss, Roberto P.. Academia Nacional de Medicina de Buenos Aires; ArgentinaFil: Bustuoabad, Oscar D.. Retired; ArgentinaFil: Ruggiero, Raúl A.. Academia Nacional de Medicina de Buenos Aires; ArgentinaFil: Prehn, Richmond T.. University Of Washington, Seattle

Retrieval of the gastric specimen following laparoscopic sleeve gastrectomy. Experience on 275 cases.

Severe obesity leads to a high incidence of complications and a decrease in life expectancy, especially among younger adults. Laparoscopic sleeve gastrectomy (LSG) first intended as the first step of biliopancreatic diversion with duodenal switch is gaining a per-se procedure role because of its effectiveness on weight loss and comorbidity resolution. Different techniques have been described for specimen extraction in LSG. In this article we report the technique adopted in 275 LSGs performed in our department. In the first 120 LSGs performed from 2007, the specimen was extracted through a mini laparotomy. In the following 155 cases the technique has been simplified: the grasped specimen has been withdrawn through the 15 mm trocar site. We registered in the fist group six cases of wound infection (5%), ten cases of hematoma (8.3%) and four cases of port site hernia (3.3%). In the second group only one case of hematoma (0.6%, p = 0.01) but no cases of wound infection (p = 0.01) or port site hernia, (p = 0.03) although we registered a specimen perforation during retrieval in 16 patients, were reported. The technique described in the 155 cases of the control group has shown to be more effective than the technique we used in the case group, allowing significantly lower operative time (112.9 ± 1.0 vs 74.9 ± 9.1 p < 0.001) and complications, and providing unchanged costs

Meta-tirosina. Un poderoso agente anti-metastásico sin efectos tóxicos colaterales detectables

La resistencia concomitante antitumoral (RC) es el fenómeno según el cual un individuo portador de tumor inhibe el crecimiento de implantes tumorales secundarios y metástasis. Si bien desde hace tiempo se sabe que la RC inducida por tumores inmunogénicos de pequeño tamaño es generada por mecanismos inmunológicos dependientes de células T, por otro lado, la manifestación más universal de la RC, generada tanto por tumores inmunogénicos como no-inmunogénicos de gran tamaño, había sido asociada con un (unos) factor sérico antitumoral cuya naturaleza permaneció elusiva por años. En un trabajo reciente, nuestro grupo de trabajo identificó este factor como la mezcla equi-molar de meta-tirosina y orto-tirosina, dos isómeros de tirosina que no están presentes en proteínas normales y que demostraron ser responsables del 90% y 10%, respectivamente, de la actividad antitumoral total del suero. En este trabajo, continuamos nuestras investigaciones demostrando que la administración periódica de meta-tirosina reducía drásticamente el número de metástasis pulmonares y hepáticas en ratones portadores de dos tumores murinos altamente metastásicos y disminuía dramáticamente la mortandad (de 100% a 25%) de ratones con metástasis ya establecidas al momento de la extirpación quirúrgica del tumor. Estos efectos anti-metastásicos se lograron aun con muy bajas concentraciones de meta-tirosina y sin efectos tóxicos perceptibles, lo que sugiere que su uso puede ayudar a diseñar nuevas y menos nocivas estrategias para el tratamiento del cáncer, especialmente aquellas destinadas a controlar el crecimiento metastásico, que es el problema más grave en la enfermedad oncológica.Concomitant tumor resistance (CR) is a phenomenon in which a tumor-bearing host is resistant to the growth of secondary tumor implants and metastasis. While former studies have indicated that T-cell dependent processes mediate CR in hosts bearing immunogenic small tumors, the most universal manifestation of CR induced by immunogenic and non-immunogenic large tumors had been associated with an antitumor serum factor that remained an enigma for many years. In a recent paper, we identified that elusive factor(s) as an equi-molar mixture of meta-tyrosine and ortho-tyrosine, two isomers of tyrosine that are not present in normal proteins and that proved to be responsible for 90% and 10%, respectively, of the total serum anti-tumor activity. In this work, we have extended our previous findings demonstrating that a periodic intravenous administrationof meta-tyrosine induced a dramatic reduction of lung and hepatic metastases generated in mice bearing two different metastatic murine tumors and decreased the rate of death from 100% up to 25% in tumor-excised mice that already exhibited established metastases at the time of surgery. These anti-metastatic effects were achieved even at very low concentrations and without displaying any detectable toxic-side effects, suggesting that the use of meta-tyrosine may help to develop new and less harmful means of managing malignant diseases, especiallythose aimed to control the growth of metastases that is the most serious problem in cancer pathology.Fil: Machuca, Damián Gabriel. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Medicina Experimental. Academia Nacional de Medicina de Buenos Aires. Instituto de Medicina Experimental; ArgentinaFil: Chiarella, Paula. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Medicina Experimental. Academia Nacional de Medicina de Buenos Aires. Instituto de Medicina Experimental; ArgentinaFil: Montagna, Daniela Romina. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Medicina Experimental. Academia Nacional de Medicina de Buenos Aires. Instituto de Medicina Experimental; ArgentinaFil: Dran, Graciela Isabel. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Medicina Experimental. Academia Nacional de Medicina de Buenos Aires. Instituto de Medicina Experimental; ArgentinaFil: Meiss, Roberto P.. Academia Nacional de Medicina de Buenos Aires; ArgentinaFil: Ruggiero, Raul Alejandro. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Medicina Experimental. Academia Nacional de Medicina de Buenos Aires. Instituto de Medicina Experimental; Argentin

High plasma uric acid concentration: causes and consequences

High plasma uric acid (UA) is a precipitating factor for gout and renal calculi as well as a strong risk factor for Metabolic Syndrome and cardiovascular disease. The main causes for higher plasma UA are either lower excretion, higher synthesis or both. Higher waist circumference and the BMI are associated with higher insulin resistance and leptin production, and both reduce uric acid excretion. The synthesis of fatty acids (tryglicerides) in the liver is associated with the de novo synthesis of purine, accelerating UA production. The role played by diet on hyperuricemia has not yet been fully clarified, but high intake of fructose-rich industrialized food and high alcohol intake (particularly beer) seem to influence uricemia. It is not known whether UA would be a causal factor or an antioxidant protective response. Most authors do not consider the UA as a risk factor, but presenting antioxidant function. UA contributes to > 50% of the antioxidant capacity of the blood. There is still no consensus if UA is a protective or a risk factor, however, it seems that acute elevation is a protective factor, whereas chronic elevation a risk for disease

Novel Blood Pressure Locus and Gene Discovery Using Genome-Wide Association Study and Expression Data Sets From Blood and the Kidney.

Elevated blood pressure is a major risk factor for cardiovascular disease and has a substantial genetic contribution. Genetic variation influencing blood pressure has the potential to identify new pharmacological targets for the treatment of hypertension. To discover additional novel blood pressure loci, we used 1000 Genomes Project-based imputation in 150 134 European ancestry individuals and sought significant evidence for independent replication in a further 228 245 individuals. We report 6 new signals of association in or near HSPB7, TNXB, LRP12, LOC283335, SEPT9, and AKT2, and provide new replication evidence for a further 2 signals in EBF2 and NFKBIA Combining large whole-blood gene expression resources totaling 12 607 individuals, we investigated all novel and previously reported signals and identified 48 genes with evidence for involvement in blood pressure regulation that are significant in multiple resources. Three novel kidney-specific signals were also detected. These robustly implicated genes may provide new leads for therapeutic innovation

New genetic loci link adipose and insulin biology to body fat distribution.

Body fat distribution is a heritable trait and a well-established predictor of adverse metabolic outcomes, independent of overall adiposity. To increase our understanding of the genetic basis of body fat distribution and its molecular links to cardiometabolic traits, here we conduct genome-wide association meta-analyses of traits related to waist and hip circumferences in up to 224,459 individuals. We identify 49 loci (33 new) associated with waist-to-hip ratio adjusted for body mass index (BMI), and an additional 19 loci newly associated with related waist and hip circumference measures (P < 5 × 10(-8)). In total, 20 of the 49 waist-to-hip ratio adjusted for BMI loci show significant sexual dimorphism, 19 of which display a stronger effect in women. The identified loci were enriched for genes expressed in adipose tissue and for putative regulatory elements in adipocytes. Pathway analyses implicated adipogenesis, angiogenesis, transcriptional regulation and insulin resistance as processes affecting fat distribution, providing insight into potential pathophysiological mechanisms

AI is a viable alternative to high throughput screening: a 318-target study

: High throughput screening (HTS) is routinely used to identify bioactive small molecules. This requires physical compounds, which limits coverage of accessible chemical space. Computational approaches combined with vast on-demand chemical libraries can access far greater chemical space, provided that the predictive accuracy is sufficient to identify useful molecules. Through the largest and most diverse virtual HTS campaign reported to date, comprising 318 individual projects, we demonstrate that our AtomNet® convolutional neural network successfully finds novel hits across every major therapeutic area and protein class. We address historical limitations of computational screening by demonstrating success for target proteins without known binders, high-quality X-ray crystal structures, or manual cherry-picking of compounds. We show that the molecules selected by the AtomNet® model are novel drug-like scaffolds rather than minor modifications to known bioactive compounds. Our empirical results suggest that computational methods can substantially replace HTS as the first step of small-molecule drug discovery

Collimation for the LHC high intensity beams

The unprecedented design intensities of the LHC require several important advances in beam collimation. With its more than 100 collimators, acting on various planes and beams, the LHC collimation system is the biggest and most performing such system ever designed and constructed. The solution for LHC collimation is explained, the technical components are introduced and the initial performance is presented. Residual beam leakage from the system is analysed. Measurements and simulations are presented which show that collimation efficiencies of better than 99.97 % have been measured with the 3.5 TeV proton beams of the LHC, in excellent agreement with expectations.peer-reviewe

Measurement of the very rare K+→π+ννˉK^+ \to \pi^+ \nu \bar\nu decay

The decay K+→π+νν¯ , with a very precisely predicted branching ratio of less than 10−10 , is among the best processes to reveal indirect effects of new physics. The NA62 experiment at CERN SPS is designed to study the K+→π+νν¯ decay and to measure its branching ratio using a decay-in-flight technique. NA62 took data in 2016, 2017 and 2018, reaching the sensitivity of the Standard Model for the K+→π+νν¯ decay by the analysis of the 2016 and 2017 data, and providing the most precise measurement of the branching ratio to date by the analysis of the 2018 data. This measurement is also used to set limits on BR(K+→π+X ), where X is a scalar or pseudo-scalar particle. The final result of the BR(K+→π+νν¯ ) measurement and its interpretation in terms of the K+→π+X decay from the analysis of the full 2016-2018 data set is presented, and future plans and prospects are reviewed