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Una molécula para que el cáncer se autodestruya

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Una molécula para que el cáncer se autodestruya

En todo tipo de cáncer hay moléculas que aceleran un crecimiento incontrolable y mortal. ¿Qué pasaría si los científicos pudieran enganchar esas moléculas con otras que hicieran que las células se autodestruyeran? ¿Qué pasaría si aquello que impulsa la supervivencia de un cáncer pudiera en su lugar activar el programa para su destrucción?

Hace algunos años, durante una caminata por un bosque de secuoyas cercano a su casa en las montañas de Santa Cruz, esa idea fue una epifanía para Gerald Crabtree, biólogo del desarrollo de la Universidad Stanford.

“Regresé corriendo a casa”, recordó, emocionado por la idea y pensando en la manera de llevarla a cabo.

Ahora, en un artículo que se publicó el 26 de julio en la revista Nature, Crabtree, uno de los fundadores de Shenandoah Therapeutics, que desarrolla medicamentos contra el cáncer, junto con Nathanael Gray, profesor de biología química y sistemas en Stanford, y sus colegas informan que lograron lo que él imaginó en aquel paseo. Aunque el concepto está muy lejos de ser un fármaco que pueda administrarse a pacientes con cáncer, podría ser un objetivo para los desarrolladores de medicamentos en el futuro.

“Es fantástico”, comentó Jason Gestwicki, profesor de química farmacéutica de la Universidad de California, en San Francisco. “Convierte algo que el cáncer necesita para mantenerse vivo en algo que lo mata, como cambiar tus vitaminas por veneno”.

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Louis Staudt, director del Centro de Genómica del Cáncer del Instituto Nacional del Cáncer, afirmó: “Esta podría ser una nueva manera de que el cáncer actúe en su contra”. Staudt escribió un editorial para acompañar el artículo de Crabtree.

Una vez que el tratamiento se desarrolle más, añadió, “me encantaría probarlo en un ensayo clínico con nuestros pacientes que hayan agotado todas las demás opciones”.

En experimentos de laboratorio con células de un cáncer en la sangre, el linfoma difuso de células B grandes, los investigadores diseñaron y construyeron moléculas que enganchaban dos proteínas: la BCL6, una proteína mutada de la que depende el cáncer para crecer y sobrevivir agresivamente, y una proteína normal de la célula que activa cualquier gen al que se acerca.

La nueva construcción, una molécula con forma de mancuerna, no se parece a nada que se haya visto en la naturaleza. La proteína BCL6, en un extremo de la mancuerna, guía a la molécula hacia los genes de muerte celular que forman parte del ADN de cada célula y se utilizan para deshacerse de las células que ya no son necesarias. Pero cuando una persona tiene un linfoma difuso de células B grandes, la proteína BCL6 desactiva esos genes de muerte celular, haciendo que las células se vuelvan casi inmortales.

Cuando la mancuerna, guiada por la proteína BCL6, se acerca a los genes que provocan la muerte celular, la proteína normal al extremo de la mancuerna arma a esos genes que provocan la muerte. A diferencia de otros procesos en la célula que pueden revertirse, la activación de los genes de la muerte celular es irreversible.

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La nueva estrategia podría mejorar la difícil tarea de usar medicamentos para bloquear a todas las moléculas que incluyan una proteína BCL6. Para matar a las células con las moléculas en forma de mancuerna, basta con cambiar el cableado solo de una parte de las moléculas con la proteína BCL6.

Según Crabtree, el concepto podría funcionar para la mitad de todos los tipos de cáncer, los cuales presentan mutaciones conocidas que dan lugar a proteínas que impulsan el crecimiento. Y como el tratamiento se basa en las proteínas mutadas producidas por las células cancerosas, podría ser sumamente específico y no afectar a las células sanas.

Crabtree explicó cuáles son las dos áreas de descubrimiento que hicieron posible este trabajo. Una es el descubrimiento de “genes impulsores”, varios cientos de genes que, al mutar, impulsan la propagación del cáncer.

La segunda es el descubrimiento de vías que conducen a la muerte en las celulas. Según Crabtree, esas vías se utilizan para eliminar células que, por alguna razón, se rebelan; son alrededor de 60.000 millones de células diarias en cada individuo.

El objetivo era lograr que las vías que impulsan el crecimiento de las células cancerosas se comunicaran con las vías silenciadas que impulsan la muerte celular, algo que normalmente no harían.

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Cuando la molécula híbrida llegó al ADN de las células, no solo activó los genes de la muerte celular, sino que hizo algo más. La molécula con la proteína BCL6 llevó a la molécula híbrida hasta otros genes que el cáncer había silenciado. La molécula híbrida volvió a activar esos genes, creando un caos interno en la célula.

“La célula nunca había experimentado algo así”, afirmó Staudt.

“La molécula con la proteína BCL6 es el principio organizador de esas células cancerosas”, explicó. Cuando su función se ve afectada por completo, “la célula pierde su identidad y dice: ‘Aquí está pasando algo muy malo. Mejor me muero’”.

Pero el principal efecto del tratamiento experimental fue activar los genes de muerte celular, comentó Crabtree. “Ese es el efecto terapéutico”, afirmó.

El grupo probó su molécula híbrida en ratones, donde parecía segura. Pero, como bien señaló Staudt: “los humanos son muy diferentes a los ratones”.

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Stuart Schreiber, catedrático de química y biología química de la Universidad de Harvard y antiguo colaborador de Crabtree concuerda en que el trabajo es “apasionante”. Pero hizo una advertencia.

Lo que Crabtree ha creado “no es un fármaco; aún le queda mucho camino por recorrer”, afirmó.

Gina Kolata escribe sobre ciencia y medicina. Ha sido dos veces finalista del premio Pulitzer y es autora de seis libros, incluyendo Mercies in Disguise: A Story of Hope, a Family’s Genetic Destiny, and The Science That Saved Them. Más de Gina Kolata


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Cluster of farmworkers diagnosed with rare animal-borne disease in Ventura County

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Cluster of farmworkers diagnosed with rare animal-borne disease in Ventura County

A cluster of workers at Ventura County berry farms have been diagnosed with a rare disease often transmitted through sick animals’ urine, according to a public health advisory distributed to local doctors by county health officials Tuesday.

The bacterial infection, leptospirosis, has resulted in severe symptoms for some workers, including meningitis, an inflammation of the brain lining and spinal cord. Symptoms for mild cases included headaches and fevers.

The disease, which can be fatal, rarely spreads from human to human, according to the U.S. Centers for Disease Control and Prevention.

Ventura County Public Health has not given an official case count but said it had not identified any cases outside of the agriculture sector. The county’s agriculture commissioner was aware of 18 cases, the Ventura County Star reported.

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The health department said it was first contacted by a local physician in October, who reported an unusual trend in symptoms among hospital patients.

After launching an investigation, the department identified leptospirosis as a probable cause of the illness and found most patients worked on caneberry farms that utilize hoop houses — greenhouse structures to shelter the crops.

As the investigation to identify any additional cases and the exact sources of exposure continues, Ventura County Public Health has asked healthcare providers to consider a leptospirosis diagnosis for sick agricultural workers, particularly berry harvesters.

Rodents are a common source and transmitter of disease, though other mammals — including livestock, cats and dogs — can transmit it as well.

The disease is spread through bodily fluids, such as urine, and is often contracted through cuts and abrasions that contact contaminated water and soil, where the bacteria can survive for months.

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Humans can also contract the illness through contaminated food; however, the county health agency has found no known health risks to the general public, including through the contact or consumption of caneberries such as raspberries and blackberries.

Symptom onset typically occurs between two and 30 days after exposure, and symptoms can last for months if untreated, according to the CDC.

The illness often begins with mild symptoms, with fevers, chills, vomiting and headaches. Some cases can then enter a second, more severe phase that can result in kidney or liver failure.

Ventura County Public Health recommends agriculture and berry harvesters regularly rinse any cuts with soap and water and cover them with bandages. They also recommend wearing waterproof clothing and protection while working outdoors, including gloves and long-sleeve shirts and pants.

While there is no evidence of spread to the larger community, according to the department, residents should wash hands frequently and work to control rodents around their property if possible.

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Pet owners can consult a veterinarian about leptospirosis vaccinations and should keep pets away from ponds, lakes and other natural bodies of water.

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Political stress: Can you stay engaged without sacrificing your mental health?

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Political stress: Can you stay engaged without sacrificing your mental health?

It’s been two weeks since Donald Trump won the presidential election, but Stacey Lamirand’s brain hasn’t stopped churning.

“I still think about the election all the time,” said the 60-year-old Bay Area resident, who wanted a Kamala Harris victory so badly that she flew to Pennsylvania and knocked on voters’ doors in the final days of the campaign. “I honestly don’t know what to do about that.”

Neither do the psychologists and political scientists who have been tracking the country’s slide toward toxic levels of partisanship.

Fully 69% of U.S. adults found the presidential election a significant source of stress in their lives, the American Psychological Assn. said in its latest Stress in America report.

The distress was present across the political spectrum, with 80% of Republicans, 79% of Democrats and 73% of independents surveyed saying they were stressed about the country’s future.

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That’s unhealthy for the body politic — and for voters themselves. Stress can cause muscle tension, headaches, sleep problems and loss of appetite. Chronic stress can inflict more serious damage to the immune system and make people more vulnerable to heart attacks, strokes, diabetes, infertility, clinical anxiety, depression and other ailments.

In most circumstances, the sound medical advice is to disengage from the source of stress, therapists said. But when stress is coming from politics, that prescription pits the health of the individual against the health of the nation.

“I’m worried about people totally withdrawing from politics because it’s unpleasant,” said Aaron Weinschenk, a political scientist at the University of Wisconsin–Green Bay who studies political behavior and elections. “We don’t want them to do that. But we also don’t want them to feel sick.”

Modern life is full of stressors of all kinds: paying bills, pleasing difficult bosses, getting along with frenemies, caring for children or aging parents (or both).

The stress that stems from politics isn’t fundamentally different from other kinds of stress. What’s unique about it is the way it encompasses and enhances other sources of stress, said Brett Ford, a social psychologist at the University of Toronto who studies the link between emotions and political engagement.

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For instance, she said, elections have the potential to make everyday stressors like money and health concerns more difficult to manage as candidates debate policies that could raise the price of gas or cut off access to certain kinds of medical care.

Layered on top of that is the fact that political disagreements have morphed into moral conflicts that are perceived as pitting good against evil.

“When someone comes into power who is not on the same page as you morally, that can hit very deeply,” Ford said.

Partisanship and polarization have raised the stakes as well. Voters who feel a strong connection to a political party become more invested in its success. That can make a loss at the ballot box feel like a personal defeat, she said.

There’s also the fact that we have limited control over the outcome of an election. A patient with heart disease can improve their prognosis by taking medicine, changing their diet, getting more exercise or quitting smoking. But a person with political stress is largely at the mercy of others.

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“Politics is many forms of stress all rolled into one,” Ford said.

Weinschenk observed this firsthand the day after the election.

“I could feel it when I went into my classroom,” said the professor, whose research has found that people with political anxiety aren’t necessarily anxious in general. “I have a student who’s transgender and a couple of students who are gay. Their emotional state was so closed down.”

That’s almost to be expected in a place like Wisconsin, whose swing-state status caused residents to be bombarded with political messages. The more campaign ads a person is exposed to, the greater the risk of being diagnosed with anxiety, depression or another psychological ailment, according to a 2022 study in the journal PLOS One.

Political messages seem designed to keep voters “emotionally on edge,” said Vaile Wright, a licensed psychologist in Villa Park, Ill., and a member of the APA’s Stress in America team.

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“It encourages emotion to drive our decision-making behavior, as opposed to logic,” Wright said. “When we’re really emotionally stimulated, it makes it so much more challenging to have civil conversation. For politicians, I think that’s powerful, because emotions can be very easily manipulated.”

Making voters feel anxious is a tried-and-true way to grab their attention, said Christopher Ojeda, a political scientist at UC Merced who studies mental health and politics.

“Feelings of anxiety can be mobilizing, definitely,” he said. “That’s why politicians make fear appeals — they want people to get engaged.”

On the other hand, “feelings of depression are demobilizing and take you out of the political system,” said Ojeda, author of “The Sad Citizen: How Politics is Depressing and Why it Matters.”

“What [these feelings] can tell you is, ‘Things aren’t going the way I want them to. Maybe I need to step back,’” he said.

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Genessa Krasnow has been seeing a lot of that since the election.

The Seattle entrepreneur, who also campaigned for Harris, said it grates on her to see people laughing in restaurants “as if nothing had happened.” At a recent book club meeting, her fellow group members were willing to let her vent about politics for five minutes, but they weren’t interested in discussing ways they could counteract the incoming president.

“They’re in a state of disengagement,” said Krasnow, who is 56. She, meanwhile, is looking for new ways to reach young voters.

“I am exhausted. I am so sad,” she said. “But I don’t believe that disengaging is the answer.”

That’s the fundamental trade-off, Ojeda said, and there’s no one-size-fits-all solution.

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“Everyone has to make a decision about how much engagement they can tolerate without undermining their psychological well-being,” he said.

Lamirand took steps to protect her mental health by cutting social media ties with people whose values aren’t aligned with hers. But she will remain politically active and expects to volunteer for phone-banking duty soon.

“Doing something is the only thing that allows me to feel better,” Lamirand said. “It allows me to feel some level of control.”

Ideally, Ford said, people would not have to choose between being politically active and preserving their mental health. She is investigating ways to help people feel hopeful, inspired and compassionate about political challenges, since these emotions can motivate action without triggering stress and anxiety.

“We want to counteract this pattern where the more involved you are, the worse you are,” Ford said.

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The benefits would be felt across the political spectrum. In the APA survey, similar shares of Democrats, Republicans and independents agreed with statements like, “It causes me stress that politicians aren’t talking about the things that are most important to me,” and, “The political climate has caused strain between my family members and me.”

“Both sides are very invested in this country, and that is a good thing,” Wright said. “Antipathy and hopelessness really doesn’t serve us in the long run.”

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Video: SpaceX Unable to Recover Booster Stage During Sixth Test Flight

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Video: SpaceX Unable to Recover Booster Stage During Sixth Test Flight

President-elect Donald Trump joined Elon Musk in Texas and watched the launch from a nearby location on Tuesday. While the Starship’s giant booster stage was unable to repeat a “chopsticks” landing, the vehicle’s upper stage successfully splashed down in the Indian Ocean.

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