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Activation of p53 tumor suppressor by antagonizing its negative regulator murine double minute (MDM)2 has been considered an attractive strategy for cancer therapy and several classes of p53-MDM2 binding inhibitors have been developed. However, these compounds do not inhibit the p53-MDMX interaction, and their effectiveness can be compromised in tumors overexpressing MDMX. Here, we identify small molecules that potently block p53 binding with both MDM2 and MDMX by inhibitor-driven homo- and/or heterodimerization of MDM2 and MDMX proteins. Structural studies revealed that the inhibitors bind into and occlude the p53 pockets of MDM2 and MDMX by inducing the formation of dimeric protein complexes kept together by a dimeric small-molecule core. This mode of action effectively stabilized p53 and activated p53 signaling in cancer cells, leading to cell cycle arrest and apoptosis. Dual MDM2/MDMX antagonists restored p53 apoptotic activity in the presence of high levels of MDMX and may offer a more effective therapeutic modality for MDMX-overexpressing cancers.

CDK1 is a nonredundant cyclin-dependent kinase (CDK) with an essential role in mitosis, but its multiple functions still are poorly understood at a molecular level. Here we identify a selective small-molecule inhibitor of CDK1 that reversibly arrests human cells at the G₂/M border of the cell cycle and allows for effective cell synchronization in early mitosis. Inhibition of CDK1 during cell division revealed that its activity is necessary and sufficient for maintaining the mitotic state of the cells, preventing replication origin licensing and premature cytokinesis. Although CDK1 inhibition for up to 24 h is well tolerated, longer exposure to the inhibitor induces apoptosis in tumor cells, suggesting that selective CDK1 inhibitors may have utility in cancer therapy.

The p53 tumor suppressor retains its wild-type conformation and transcriptional activity in half of all human tumors, and its activation may offer a therapeutic benefit. However, p53 function could be compromised by defective signaling in the p53 pathway. Using a small-molecule MDM2 antagonist, nutlin-3, to probe downstream p53 signaling we find that the cell-cycle arrest function of the p53 pathway is preserved in multiple tumor-derived cell lines expressing wild-type p53, but many have a reduced ability to undergo p53-dependent apoptosis. Gene array analysis revealed attenuated expression of multiple apoptosis-related genes. Cancer cells with mdm2 gene amplification were most sensitive to nutlin-3 in vitro and in vivo, suggesting that MDM2 overexpression may be the only abnormality in the p53 pathway of these cells. Nutlin-3 also showed good efficacy against tumors with normal MDM2 expression, suggesting that many of the patients with wild-type p53 tumors may benefit from antagonists of the p53-MDM2 interaction.

La cantidad de muertes violentas en México ha venido creciendo durante los últimos años, lo que ha ocasionado enormes retos en las políticas públicas, específicamente en las relacionadas con la seguridad pública, los servicios de salud y las aseguradoras. En general, una muerte violenta es una tragedia que, con frecuencia, puede ser evitada. Además, dicha pérdida no sólo afecta a la víctima y a sus familiares, ya que repercute en toda la sociedad. En efecto, al considerar esta problemática, y utilizando las ecuaciones de ingreso de Mincer, observamos que se han perdido cuantiosas vidas de trabajadores (potenciales o en activo), por lo que la sociedad ha perdido el ingreso y el consumo potenciales de las personas fallecidas. Por tal razón, en este artículo estimamos las pérdidas económicas causadas por las muertes violentas, esperando coadyuvar a aumentar la conciencia sobre la urgencia de delinear e instrumentar políticas públicas que disminuyan este tipo de fallecimientos que, insistimos, son evitables. The number of violent deaths in Mexico has been increasing in recent years. This has brought a great challenge to public policies, specifically those related to public safety, health services, Tand insurance. A violent death is a senseless tragedy that could be avoided, and it is incorrect to think that this death exclusively affects the victim and their family members. In reality, it affects the whole of society. When considering this problem using Mincer's income equations, we observe that the lives of workers (potential or active) have been lost and that society has lost the income and potential consumption of the deceased. For this reason, in this article we intend to assess the economic losses caused by violent demises, hoping to help increase awareness that public policies are urgently needed to reduce these types of preventable deaths.

Background Hormone therapy is the standard of care for newly diagnosed or recurrent prostate cancers. It uses anti-androgen agents, castration, or both to eliminate cancer promoting effect of testicular androgen. The p53 tumor suppressor controls a major pathway that can block cell proliferation or induce apoptosis in response to diverse forms of oncogenic stress. Activation of the p53 pathway in cancer cells expressing wild-type p53 has been proposed as a novel therapeutic strategy and recently developed MDM2 antagonists, the nutlins, have validated this in preclinical models of cancer. The crosstalk between p53 and androgen receptor (AR) signaling suggest that p53 activation could augment antitumor outcome of androgen ablation in prostate cancer. Here, we test this hypothesis in vitro and in vivo using the MDM2 antagonist, nutlin-3 and the p53 wild-type prostate cancer cell line, LNCaP. Results Using charcoal-stripped serum as a cellular model of androgen deprivation, we show an increased apoptotic effect of p53 activation by nutlin-3a in the androgen-dependent LNCaP cells and to a lesser extent in androgen-independent but responsive 22Rv1 cell line. This effect is due, at least in part, to an enhanced downregulation of AR expression by activated p53. In vivo, androgen deprivation followed by two weeks of nutlin administration in LNCaP-bearing nude mice led to a greater tumor regression and dramatically increased survival. Conclusions Since majority of prostate tumors express wild-type p53, its activation by MDM2 antagonists in combination with androgen depletion may offer an efficacious new approach to prostate cancer therapy.

El artículo examina el impacto del gasto público rural destinado a los Programas de Fomento Productivo Agropecuario (PFPA) sobre la producción de cuatro bienes básicos de la canasta alimentaria mexicana durante 1986-2023: carne de ave, carne de bovino, carne de porcino y leche de vaca. Se empleó un modelo de vectores autorregresivos (VAR) que analizó la relación temporal entre los pfpa y la producción de carnes y leche. En el periodo, se ubicaron dos grandes etapas de la política agrícola en México; la primera, previa a 2019, que siguió los parámetros de la apertura comercial de la década de 1980 y que renunció al objetivo de la soberanía alimentaria; la segunda, posterior a 2019, que lo retomó nuevamente. En ambas, los pfpa fueron fundamentales en la política de gasto. Los resultados del modelo muestran una relación débil entre el gasto asignado a los PFPA y la producción de carnes y leche. RURAL PUBLIC SPENDING AND MEAT AND MILK PRODUCTION IN MEXICO, 1986-2023 ABSTRACT This article examines the impact of rural public spending on Agricultural Production Development Programs (APDPs) on the production of four basic commodities of the Mexican food basket during the period 1986-2023: Beef, pork, poultry, and cow’s milk. A Vector Autoregressive (VAR) model was used to analyze the temporal relationship between the apdps and the production of meat and milk. During this period, there were two major phases of agricultural policy in Mexico: The first, before 2019, which followed the parameters of trade liberalization of the 1980s and abandoned the objective of food sovereignty; and the second, after 2019, which resumed it. In both cases, apdps were central to expenditure policies. The model results show a weak relationship between spending on APDPs and meat and milk production.

Stapled α−helical peptides have emerged as a promising new modality for a wide range of therapeutic targets. Here, we report a potent and selective dual inhibitor of MDM2 and MDMX, ATSP-7041, which effectively activates the p53 pathway in tumors in vitro and in vivo. Specifically, ATSP-7041 binds both MDM2 and MDMX with nanomolar affinities, shows submicromolar cellular activities in cancer cell lines in the presence of serum, and demonstrates highly specific, on-target mechanism of action. A high resolution (1.7-Å) X-ray crystal structure reveals its molecular interactions with the target protein MDMX, including multiple contacts with key amino acids as well as a role for the hydrocarbon staple itself in target engagement. Most importantly, ATSP-7041 demonstrates robust p53-dependent tumor growth suppression in MDM2/MDMX-overexpressing xenograft cancer models, with a high correlation to on-target pharmacodynamic activity, and possesses favorable pharmacokinetic and tissue distribution properties. Overall, ATSP-7041 demonstrates in vitro and in vivo proof-of-concept that stapled peptides can be developed as therapeutically relevant inhibitors of protein–protein interaction and may offer a viable modality for cancer therapy.

El artículo examina el impacto del gasto público rural destinado a los Programas de Fomento Productivo Agropecuario (PFPA) sobre la producción de cuatro bienes básicos de la canasta alimentaria mexicana durante 1986-2023: carne de ave, carne de bovino, carne de porcino y leche de vaca. Se empleó un modelo de vectores autorregresivos (VAR) que analizó la relación temporal entre los PFPA y la producción de carnes y leche. En el periodo, se ubicaron dos grandes etapas de la política agrícola en México; la primera, previa a 2019, que siguió los parámetros de la apertura comercial de la década de 1980 y que renunció al objetivo de la soberanía alimentaria; la segunda, posterior a 2019, que lo retomó nuevamente. En ambas, los PFPA fueron fundamentales en la política de gasto. Los resultados del modelo muestran una relación débil entre el gasto asignado a los PFPA y la producción de carnes y leche. This article examines the impact of rural public spending on Agricultural Production Development Programs (APDPS) on the production of four basic commodities of the Mexican food basket during the period 1986-2023: Beef, pork, poultry, and cow’s milk. A Vector Autoregressive (VAR) model was used to analyze the temporal relationship between the APDPS and the production of meat and milk. During this period, there were two major phases of agricultural policy in Mexico: The first, before 2019, which followed the parameters of trade liberalization of the 1980s and abandoned the objective of food sovereignty; and the second, after 2019, which resumed it. In both cases, APDPS were central to expenditure policies. The model results show a weak relationship between spending on APDPS and meat and milk production.

Stapled α-helical peptides have emerged as a promising new modality for a wide range of therapeutic targets. Here, we report a potent and selective dual inhibitor of MDM2 and MDMX, ATSP-7041, which effectively activates the p53 pathway in tumors in vitro and in vivo. Specifically, ATSP-7041 binds both MDM2 and MDMX with nanomolar affinities, shows submicromolar cellular activities in cancer cell lines in the presence of serum, and demonstrates highly specific, on-target mechanism of action. A high resolution (1.7-A) X-ray crystal structure reveals its molecular interactions with the target protein MDMX, including multiple contacts with key amino acids as well as a role for the hydrocarbon staple itself in target engagement. Most importantly, ATSP-7041 demonstrates robust p53-dependent tumor growth suppression in MDM2/MDMX-overexpressing xenograft cancer models, with a high correlation to on-target pharmacodynamic activity, and possesses favorable pharmacokinetic and tissue distribution properties. Overall, ATSP-7041 demonstrates in vitro and in vivo proof-of-concept that stapled peptides can be developed as therapeutically relevant inhibitors of protein-protein interaction and may offer a viable modality for cancer therapy. [PUBLICATION ABSTRACT]