Fc-Silent Anti-TIGIT Antibodies Potentiate Antitumor Immunity without Depleting Regulatory T Cells.

T-cell immunoreceptor with immunoglobulin and immunoreceptor tyrosine-based inhibitory motif domains (TIGIT) is an inhibitory receptor on immune cells that outcompetes an activating receptor, CD226, for shared ligands. Tumor-infiltrating lymphocytes express TIGIT and CD226 on regulatory T cells (Treg) and on CD8+ T cells with tumor-reactive or exhausted phenotypes, supporting the potential of therapeutically targeting TIGIT to enhance antitumor immunity. To optimize the efficacy of therapeutic antibodies against TIGIT, it is necessary to understand IgG Fc (Fcγ) receptor binding for therapeutic benefit. In this study, we showed that combining Fc-enabled (Fce) or Fc-silent (Fcs) anti-TIGIT with antiprogrammed cell death protein 1 in mice resulted in enhanced control of tumors by differential mechanisms: Fce anti-TIGIT promoted the depletion of intratumoral Treg, whereas Fcs anti-TIGIT did not. Despite leaving Treg numbers intact, Fcs anti-TIGIT potentiated the activation of tumor-specific exhausted CD8+ populations in a lymph node-dependent manner. Fce anti-TIGIT induced antibody-dependent cell-mediated cytotoxicity against human Treg in vitro, and significant decreases in Treg were measured in the peripheral blood of patients with phase I solid tumor cancer treated with Fce anti-TIGIT. In contrast, Fcs anti-TIGIT did not deplete human Treg in vitro and was associated with anecdotal objective clinical responses in two patients with phase I solid tumor cancer whose peripheral Treg frequencies remained stable on treatment. Collectively, these data provide evidence for pharmacologic activity and antitumor efficacy of anti-TIGIT antibodies lacking the ability to engage Fcγ receptor. SIGNIFICANCE: Fcs-silent anti-TIGIT antibodies enhance the activation of tumor-specific pre-exhausted T cells and promote antitumor efficacy without depleting T regulatory cells.

Quantitative EEG analysis in typical absence seizures: unveiling spectral dynamics and entropy patterns.

A typical absence seizure is a generalized epileptic event characterized by a sudden, brief alteration of consciousness that serves as a hallmark for various generalized epilepsy syndromes. Distinguishing between similar interictal and ictal electroencephalographic (EEG) epileptiform patterns poses a challenge. However, quantitative EEG, particularly spectral analysis focused on EEG rhythms, shows potential for differentiation. This study was designed to investigate discernible differences in EEG spectral dynamics and entropy patterns during the pre-ictal and post-ictal periods compared to the interictal state. We analyzed 20 EEG ictal patterns from 11 patients with confirmed typical absence seizures, and assessed recordings made during the pre-ictal, post-ictal, and interictal intervals. Power spectral density (PSD) was used for the quantitative analysis that focused on the delta, theta, alpha, and beta bands. In addition, we measured EEG signal regularity using approximate (ApEn) and multi-scale sample entropy (MSE). Findings demonstrate a significant increase in delta and theta power in the pre-ictal and post-ictal intervals compared to the interictal interval, especially in the posterior brain region. We also observed a notable decrease in entropy in the pre-ictal and post-ictal intervals, with a more pronounced effect in anterior brain regions. These results provide valuable information that can potentially aid in differentiating epileptiform patterns in typical absence seizures. The implications of our findings are promising for precision medicine approaches to epilepsy diagnoses and patient management. In conclusion, our quantitative analysis of EEG data suggests that PSD and entropy measures hold promise as potential biomarkers for distinguishing ictal from interictal epileptiform patterns in patients with confirmed or suspected typical absence seizures.

Forest fire probability under ENSO conditions in a semi-arid region: a case study in Guanajuato.

Fires can pose a threat to forest ecosystems when those ecosystems are not fire-adapted or when forest community conditions make them vulnerable to wildfires. Thus, investigating fire-prone environmental conditions is urgently needed to create action plans that preserve these ecosystems. In this sense, climate variables can determine the environmental conditions favorable for forest fires. Our study confirms that vapor pressure deficit (VPD) is an essential climate indicator for forest fires, as it is related to maximum temperatures and low humidity, representing the stress conditions for vegetation prone to fires. This study explores the extent to which ENSO phases can modulate climatic conditions that lead to high VPD over Guanajuato, a semi-arid region in central Mexico, during the dry season (March-April-May). Using fire occurrence data from MODIS (2000-2019) and Landsat 5 (1998-1999), we developed a climatic probability model for the occurrence of forest fires using VPD estimated from ERA5 reanalysis for each ENSO phase. We found that VPD and the occurrence of forest fires were higher during El Niño than under Neutral and La Niña years, with a higher risk of forest fire occurrence in Guanajuato's southern region. This study concludes that it is necessary to implement regional and local fire management plans, especially where the largest number of natural protected areas is located.

Exploratory Study: Excessive Iron Supplementation Reduces Zinc Content in Pork without Affecting Iron and Copper.

The aim of this work was to determine in an exploratory manner the effect of excessive iron supplementation on iron, zinc, and copper contents in pork and pork offal. Pigs averaging 50 days in age and 15 ± 1.3 kg body weight were allocated to a control group (500 ppm dietary Fe) and a supplemental group (3000 ppm dietary Fe). After an iron supplementation period of 60 days, blood samples were analyzed to determine iron biomarkers, serum copper, and zinc contents. Animals were slaughtered to assess total iron, non-heme iron, heme iron, zinc, and copper contents in samples of nine meat cuts and some offal. Iron supplementation improved the iron status in pigs with increased hemoglobin and hematocrit, but did not affect serum levels of iron, zinc, and copper. Iron supplementation did not affect the heme and non-heme iron contents of the different meat cuts. Zinc contents decreased by 32-55% in meat cuts, where iron content increased in the liver, spleen, kidneys, and pancreas. No differences of zinc and copper were observed in offal samples. High concentrations of iron supplementation reduce zinc content in pork.

Trazabilidad metrológica de un estándar secundario a un estándar primario de ciclosporina para pruebas de biodisponibilidad / Metrological traceability of a secondary standard to a primary cyclosporine standard for biodability tests

INTRODUCCIÓN: el proceso de trazabilidad metrológica de un estándar secundario a uno primario es una propiedad del resultado de una medición o del valor de un estándar, por la cual se puede relacionar a referencias establecidas, usualmente nacionales o internacionales, a través de una cadena ininterrumpida de comparaciones, todas las cuales tienen incertidumbres determinadas. OBJETIVO: realizar la trazabilidad de un estándar secundario a uno primario de ciclosporina y de esta manera asegurar la calidad y pureza del mismo. MÉTODOS: se utilizaron los siguientes métodos: descripción organoléptica, solubilidad, identificación y cuantificación por Cromatografía Líquida de alta resolución (HPLC) en fase reversa. RESULTADOS: el estándar secundario de ciclosporina, cumplió con todas las especificaciones referidas a descripción organoléptica, solubilidad, identificación y se obtuvo una pureza de 97,5% utilizando un estándar primario cuyo título es de 98,5 %. CONCLUSIÓN: se realizó la trazabilidad metrológica de un estándar secundario a un estándar primario para poder utilizarlo como estándar de trabajo, garantizando el título del mismo. Esta propiedad es uno de los pilares para que los resultados de medida sean comparables entre sí, independientemente del lugar y tiempo en el que se hayan realizado, facilitando su aceptación universal y reduciendo las potenciales barreras técnicas al comercio.

INTRODUCTION: the metrological traceability process from a secondary standard to a primary one is a property of the result of a measurement or the value of a standard, by which it can be related to established references, usually national or international, through an uninterrupted chain of comparisons, all of which have certain uncertainties. OBJECTIVE: to carry out the traceability of a secondary standard to a primary one of cyclosporine and in this way to ensure its quality and purity. METHODS: the following methods were used: organoleptic description, solubility, identification and quantification by reversed phase High Performance Liquid Chromatogra- phy (HPLC). RESULTS: the secondary cyclosporine standard met all the specifications referred to organoleptic description, solubility, identification and a purity of 97.5% was obtained using a primary standard whose titer is 98.5%. CONCLUSION: the metrological traceability of a secondary standard to a primary standard was carried out in order to be able to use it as a working standard, guaranteeing its title. This property is one of the pillars for the measurement results to be comparable with each other, regardless of the place and time in which they have been carried out, facilitating their universal acceptance and reducing potential technical barriers to trade.

[Prevalence of endometriosis in 287 women undergoing surgical sterilization in Santiago Chile]. / Prevalencia de la endometriosis en mujeres sometidas a esterilización quirúrgica laparoscópica en un hospital de Santiago de Chile.

BACKGROUND: The clinical manifestations of endometriosis are infertility, dysmenorrhea, sexuality disturbances, and chronic pelvic pain. It is the cause of 30 to 50% of infertility cases. In developed countries, the prevalence of endometriosis among women undergoing surgical sterilization is approximately 6%. AIM: To determine the prevalence of endometriosis among women with proven fertility in Santiago de Chile. MATERIAL AND METHODS: Review of surgical protocols of 287 women aged 25 to 49 years, subjected to a surgical sterilization between 2007 and 2011. RESULTS: Endometriosis was found in 14 of the 287 women (4.9%). In spite of being asymptomatic, five of the 14 women with endometriosis were classified as severe, due to the presence of at least one endometrioma. In order of frequency, the most commonly affected anatomical sites were the ovary, the peritoneum, the posterior cul-de-sac and uterosacral ligaments. CONCLUSIONS: Our findings are very similar to those found elsewhere and suggest that fertile women could better tolerate endometriosis than their infertile counterparts.

Prevalencia de la endometriosis en mujeres sometidas a esterilización quirúrgica laparoscópica en un hospital de Santiago de Chile / Prevalence of endometriosis in 287 women undergoing surgical sterilization in Santiago Chile

Background: The clinical manifestations of endometriosis are infertility, dysmenorrhea, sexuality disturbances, and chronic pelvic pain. It is the cause of 30 to 50% of infertility cases. In developed countries, the prevalence of endometriosis among women undergoing surgical sterilization is approximately 6%. Aim: To determine the prevalence of endometriosis among women with proven fertility in Santiago de Chile. Material and Methods: Review of surgical protocols of 287 women aged 25 to 49 years, subjected to a surgical sterilization between 2007 and 2011. Results: Endometriosis was found in 14 of the 287 women (4.9%). In spite of being asymptomatic, five of the 14 women with endometriosis were classified as severe, due to the presence of at least one endometrioma. In order of frequency, the most commonly affected anatomical sites were the ovary, the peritoneum, the posterior cul-de-sac and uterosacral ligaments. Conclusions: Our findings are very similar to those found elsewhere and suggest that fertile women could better tolerate endometriosis than their infertile counterparts.

Iron, copper, and zinc transport: inhibition of divalent metal transporter 1 (DMT1) and human copper transporter 1 (hCTR1) by shRNA.

Iron (Fe), copper (Cu), and zinc (Zn) fulfill various essential biological functions and are vital for all living organisms. They play important roles in oxygen transport, cell growth and differentiation, neurotransmitter synthesis, myelination, and synaptic transmission. Because of their role in many critical functions, they are commonly used in food fortification and supplementation strategies globally. To determine the involvement of divalent metal transporter 1 (DMT1) and human copper transporter 1 (hCTR1) on Fe, Cu, and Zn uptake, Caco-2 cells were transfected with four different shRNA plasmids to selectively inhibit DMT1 or hCTR1 transporter expression. Fe and Cu uptake and total Zn content measurements were performed in shRNA-DMT1 and shRNA-hCTR1 cells. Both shRNA-DMT1 and shRNA-hCTR1 cells had lower apical Fe uptake (a decrease of 51% and 41%, respectively), Cu uptake (a decrease of 25.8% and 38.5%, respectively), and Zn content (a decrease of 23.1% and 22.7%, respectively) compared to control cells. These results confirm that DMT1 is involved in active transport of Fe, Cu, and Zn although Zn showed a different relative capacity. These results also show that hCTR1 is able to transport Fe and Zn.

Searching for specific responses to copper exposure: an in vitro copper challenge in peripheral mononuclear cells.

Acute and chronic cellular responses to changes in copper availability are not clear when these changes are mild to moderate, as what often occur in human daily life. The aims of the study were to develop an in vitro copper challenge in peripheral mononuclear cells (PMNCs) obtained from healthy individuals with different preconditioning copper treatments, and measure copper and iron content, and MT2A and TfR mRNA abundance after the copper challenge. (1) Screening using clinical and biochemical indicators defined healthy participants, who received 8 mg Cu/day (copper sulfate) or placebo for 2 months. (2) Mononuclear cells were obtained on days 0, 2 (acute changes), and 60 (chronic changes). (3) Cells were challenged with a 1, 5, and 20 µM Cu-histidine for 20 h, at T0, T2, and T60. Cells from both supplemented and placebo individuals showed a clear trend to increase copper content when there was more copper in the media. Increases were greater in the supplemented group, larger with 20 µM Cu (p < 0.02, one-way ANOVA), and mostly not significant when incubated with 5 µM Cu. By two-way ANOVA, differences were significant by treatment and by time (both p < 0.001). Differences between T0/T2 and T0/T60 were also significant (both p < 0.001). Changes of iron content were significant by treatment and time (two-way ANOVA); mRNA relative abundance of MT2A changed significantly and paralleled those of copper concentration, but TfR transcripts did not change. An in vitro challenge of PMNC showed specific changes of cellular copper and MT2A, while changes of iron content and TfR mRNA abundance were not consistent. PMNCs appear as good candidates to assess changes of cellular copper availability. That results differed after acute (T2) and chronic (T60) supplementation suggests that acute and chronic changes are handled differently by these cells.

Pharmacokinetics of a single oral dose of 1.5-mg levonorgestrel when administered as 750-mug tablets or as 30-microg minipills.

We examined the pharmacokinetics of a single dose of 1.5 mg of levonorgestrel when administered orally in two different formulations: two tablets of 0.75 mg or 50 minipills of 30 microg of levonorgestrel. Bioavailability of levonorgestrel with minipills was comparable to that with levonorgestrel tablets. These findings suggest that levonorgestrel-containing minipills can be considered as an alternative to standard levonorgestrel tablets for use in emergency contraception.

Pharmacokinetics and endometrial tissue levels of levonorgestrel after administration of a single 1.5-mg dose by the oral and vaginal route.

OBJECTIVE: To determine the pharmacokinetics and endometrial tissue levels of levonorgestrel when taken as a single dose of 1.5 mg either orally or vaginally by healthy women in the periovulatory phase of their menstrual cycle. DESIGN: Prospective randomized study. SETTING: Academic research institution. PATIENT(S): Thirty women with regular cycles allocated to control (n = 5), oral (n = 13), and vaginal (n = 12) groups. INTERVENTION(S): Blood samples were drawn before (0 time) and at 0.5, 1, 2, 4, 6, 8, 24, 48, and 168 hours after levonorgestrel administration. Endometrial samples were collected 24 and 168 hours after levonorgestrel administration. MAIN OUTCOME MEASURE(S): Plasma and endometrial tissue levels of levonorgestrel. RESULT(S): Plasma concentrations of levonorgestrel were significantly greater during the first 48 hours after oral administration. However, 7 days after levonorgestrel administration, the plasma levels were similar for both treatments (3-5 nmol/L). Compared with vaginal administration, oral administration resulted in higher peak plasma concentrations (Cmax 64 vs. 10.7 nmol/L), with a shorter time to reach the maximal concentrations (Tmax 1.4 vs. 6.6 hours) and with a greater AUC (509 vs. 175 nmol/L). Interestingly, the half-life of levonorgestrel was shorter after oral administration (25 hours vs. 32.6 hours). Levonorgestrel tissue concentrations were not related to the plasma levels. Levonorgestrel values tended to be higher in endometrial tissue after vaginal administration. The ratio between plasma and endometrial concentrations of levonorgestrel differed significantly between the groups. CONCLUSION(S): These data indicate that orally administered levonorgestrel achieves higher plasma levels sooner than vaginally administered levonorgestrel. However, plasma levels after vaginal administration are more sustained and were likely to be sufficient for ovarian suppression. Therefore, the vaginally administered levonorgestrel could be considered as an alternative option for emergency contraception.

Brote de triquinosis en la comuna de Purranque X Región, Chile: octubre/noviembre 1992 / Outbreak of trichinosis in Purranque county X Region, Chile: october/november 1992

An outbreak of trichinosis occurred in Purranque county, X Region, Chile, between october and november of 1992, which involved 36 persons. The incubation period, determinated by the clinical picture and laboratory assays, fluctuated between 10 and 12 days, myalgias (88,9 for percent) and palpebral oedema (86,1 por percent) were the most important symptoms, followed by fever (44,4 for percent) and headache (33,3 for percent). Eosinophils count ranged from two to 42 for percent the first week, and this value raised to 55 for percent the second week of the outbreak. Anti-trichinella spiralis antibodies were determinated by some serological tests such as: precipitin test (PT), bentonite flocculation test (BFT) and indirect hemagglutination test (IHAT) in sera IHAT (21,4 for percent) and BFT (3,6 for percent). After 15 days, the three tests were perfomed in sera from 12 patients. At that time, the positivity was elevated in all of them: PT (100,0 for percent), BFT (66,7 for percent) and IHAT (91,7 for percent). It is believed that the outbreak had its origin in infected pork meat that was consumed raw or insufficiently cooked without a previous veterinary inspection