Publisher Health

Researchers in Purdue University’s College of Pharmacy are leveraging the dual roles played by an enzyme found in both cancer cells and T cells to create a novel cancer immunotherapy compound.
Zhong-Yin Zhang leads a team that has developed TP1L, a highly potent and selective small-molecule degrader. It targets the enzyme TC-PTP, or T-cell protein tyrosine phosphatase, in cells and deletes it.
He said recent studies have shown that deleting TC-PTP in certain tumor cells promotes antigen presentation, which alerts the immune system to the presence of tumor cells. Other studies have shown that the loss of the enzyme in T cells stimulates the activation and reproduction of T cells, which direct immune cells to fight and destroy tumor cells.
Zhang is head of the Borch Department of Medicinal Chemistry and Molecular Pharmacology, Distinguished Professor of Medicinal Chemistry, the Robert C. and Charlotte P. Anderson Chair in Pharmacology, a member of Purdue Institute for Cancer Research, and director of the Purdue Institute for Drug Discovery. The research has been published in the peer-reviewed journal Chemical Science of the Royal Society of Chemistry.
Expanding immunotherapy options
Cancer immunotherapy is a treatment that uses the body’s immune system to find and destroy tumor cells rather than introducing pharmaceutical compounds that attack the tumor cells themselves.
Zhang said alternatives to current immunotherapy must be developed.

“Current immunotherapy approaches are effective only in 15% of the patient population,” he said. “The potency of current immunotherapy agents can be readily diminished as the cancer metastasizes and the genome alters. Also, current immunotherapy has been associated with substantial expenses and various toxicities, including neurological events.”
Zhang said TC-PTP’s dual roles make it an attractive target for developing novel cancer immunotherapy agents.
“Targeting TC-PTP with the small-molecule degraders represents an alternative approach to increase tumor antigen presentation and alleviate the inhibitory constraints on immune cells in the tumor microenvironment for improved immunotherapy,” he said.
Creating and validating TP1L
Zhang and his team used rational design and systematic screening to discover TP1L, which he called “the first highly potent and selected TC-PTP degrader.”
“TP1L was developed by leveraging the cell’s ubiquitin-proteasome machinery to achieve selective degradation of TC-PTP,” Zhang said. “Through TC-PTP degradation and augmentation of TC-PTP substrate phosphorylation, TP1L can increase interferon signaling in tumor cells and intensify T-cell activation, therefore enhancing tumor-killing efficacy of T cells.”
After T cells kill the tumor cells, TP1L remains intact and can catalyze multiple additional rounds of TC-PTP degradation.

“We surmise that TP1L not only provides a unique opportunity for in-depth interrogation of TC-PTP biology but also serves as an excellent starting point for the development of novel immunotherapeutic agents targeting TC-PTP,” Zhang said.
Further developments
Zhang and his team will continue to develop TP1L at Purdue.
“We will continue to improve the potency and drug properties of the TP1L and expand its utility of the degraders on different cancers,” Zhang said.

An existing drug that targets senescent, or sleeping cells could provide the answer to treating lower back pain, according to a new study.
The research, published today as a Reviewed Preprint in eLife, advances our understanding of the role of senescent osteoclasts — cells that break down and remove damaged bone tissue — in the development of lower back pain, which affects 8 in 10 people at some point in their lives. eLife’s editors say the study provides compelling evidence that an existing drug, Navitoclax, can eliminate senescent osteoclasts in mice and, in doing so, markedly reduce spinal pain.
Osteoclasts resorb and break down bone tissue as part of the body’s natural bone remodelling and maintenance process. When these cells become senescent, they no longer function properly, which can lead to problems with bone maintenance and repair.
“It’s previously been shown that senescence promotes age-related musculoskeletal diseases such as osteoporosis, and removing senescent cells from degenerated vertebral discs restores the intervertebral disc structure,” explains lead author Dayu Pan, Postdoctoral Research Fellow in the Departments of Orthopedic Surgery and Biomedical Engineering, Johns Hopkins University School of Medicine, US. “We previously found that osteoclasts cause the endplates between each vertebra and disc to become porous, allowing infiltration of new nerves that cause lower back pain. In this study, we set out to test whether this is caused by a specific group of senescent osteoclasts and whether eliminating these osteoclasts could reduce the pain.”
The research team first set out to identify whether senescent osteoclasts were present in the porous endplates of vertebrae in mice with two types of spine hypersensitivity — one caused by ageing and the other caused by lumbar spine instability. They tested for the simultaneous presence of two markers within the bone — ‘TRAP’ which is a hallmark of osteoclasts, and p16, used to identify senescent cells. In both types of spinal degeneration, they saw a strong association between the presence of senescent osteoclasts and the degree of degeneration and spine hypersensitivity.
Next, they explored whether a drug called Navitoclax, which targets senescent cells, could eliminate senescent osteoclasts and reduce spinal hypersensitivity. As hoped, the treatment caused a significant reduction in senescent osteoclasts compared to untreated mice, as well as reduced pain and increased activity in mice with both types of spine degeneration.
Spinal scans and microscopic examination of bone tissue confirmed there was reduced degeneration and porosity within the endplates, as well as reduced separation between them, in the treated mice. This suggests the anti-senescence drug can prevent the degeneration and remodelling associated with ageing or spine instability.
Finally, because porous endplates allow new nerves to grow into the endplate bone, causing sensitivity, the authors looked at whether senescent osteoclasts play a role in this process. They tested for two markers of nerve fibres in the endplates of mice, as well as markers of new blood vessels, and found that mice treated with the anti-senescence drug had fewer nerves and blood vessels within the endplate than untreated mice. This suggests there is an ongoing dysfunctional production of new bone tissue within the spinal endplate in the ageing or injured spine, and that treatment to remove the senescent osteoclasts could halt this process.
Taken together, these findings suggest a potential role for anti-senescent drugs such as Navitoclax in treating spine pain, but this would need to be further evaluated in clinical trials before the treatment could be used in patients with lower back pain.
“Osteoclasts are the principal bone resorbing cells essential for bone remodelling and skeletal development, but we have shown that osteoclasts in the endplate of the spinal column undergoes senescence, leading to nerve growth and spine pain,” concludes senior author Xu Cao, Professor of Orthopedic Surgery, Department of Orthopedic Surgery and Department of Biomedical Engineering, Johns Hopkins University School of Medicine. “Our findings suggest that depletion of these senescent osteoclasts, perhaps by use of existing drugs, could represent a new strategy in the treatment of lower back pain.”

An international team has for the first time researched the longevity of neutralizing antibodies in HIV-1-infected people. Currently, it is assumed that an HIV-1 vaccine can only be effective if it produces these antibodies in vaccinated humans. The findings improve understanding of the dynamics of such antibodies and are an important building block for further research into an HIV-1 vaccine. Professor Dr Florian Klein, Director of the Institute of Virology at the University Hospital Cologne, and Dr Dr Philipp Schommers, Head of the Laboratory for Antiviral Immunity at Department I of Internal Medicine of the University Hospital Cologne, were involved in the study. The publication was published under the title ‘Dynamics and durability of HIV-1 neutralization are determined by viral replication’ in the journal Nature Medicine.
Dr Dr Schommers, first author of the study, reports: “We were able to show that the HIV-1 neutralization activity in patients strongly depends on the amount of virus in patients. While this dependence could be investigated in other infectious diseases, such as COVID-19, shortly after the initial description of the disease, the longevity of neutralizing antibodies in HIV-1 had not yet been shown in large studies.”
Despite effective drugs that are the basis for treating the HIV-1 infection and can effectively prevent the transmission of the virus, over 1.2 million people are infected with HIV every year. Therefore, the development of an effective HIV-1 vaccine is still being intensely researched. So-called broadly neutralizing antibodies (bNAbs) can prevent HIV-1 infection. Researchers are trying to induce such bNAbs through a vaccination in humans. However, this has proven to be extremely difficult. Therefore, vaccines that allow the formation of bNAbs in humans have not yet been developed. It is also unclear how long such broadly neutralizing antibodies remain in humans. However, this knowledge is extremely important in developing successful strategies for an HIV-1 vaccination.
The researchers led by Professor Klein and Dr Schommers have therefore investigated the HIV-1 antibody response in more than 2,300 patients from Germany, Tanzania, Cameroon and Nepal. They were able to identify various factors that cause patients to form neutralizing antibodies naturally. In addition, they identified so-called ‘elite neutralizers’, i.e. HIV-1-infected individuals who build up a very potent and broadly neutralizing antibody response. When the international research team examined HIV-1-infected individuals over time, it was then able to find out with what dynamics HIV-1 neutralizing antibodies can be sustained or the concentration of these antibodies can be further decreased in the blood. Here it was shown that the antibody response in these patients decreases over the years, but in them highly potent bNAbs are detectable even after years. This is an important finding and indicates that a possible HIV-1 vaccine can trigger a permanent vaccine response.

Cooking and recipe demonstrations encourage healthy eating and adoption of unfamiliar foods by class participants. The research brief shared in the Journal of Nutrition Education and Behavior, published by Elsevier, demonstrates that valuable input by peer educators can be obtained through a hybrid home-use testing method.
The process of recipe development involves sensory evaluation about the appearance, aroma, taste, texture, and flavor of the food. Although a controlled laboratory setting is the gold standard for evaluation because of consistent preparation and presentation of food, bringing peer educators to a central location results in time and financial constraints.
Corresponding author Ginnefer O. Cox, PhD, RD, Department of Nutritional Sciences, College of Family and Consumer Sciences, University of Georgia, explained, “Peer educators are key stakeholders in the recipe development process because of their close relationship with the community and their hands-on involvement with recipe demonstrations.”
For this study, 40 peer educators signed up to select from eight recipes to prepare over a four-week period. They were provided detailed recipes, non-perishable ingredients, but shopped for the perishable ingredients. They completed two surveys per recipe, preparing the recipe following the first survey. The presurvey (first survey) asked questions about their perceived acceptance of the recipe title, appearance, flavor, texture, and likelihood of peer educators preparing the recipe at home or as a food demonstration for Food Talk. Food Talk is a direct, evidence-based initiative of the University of Georgia using the Expanded Food and Nutrition Education Program and SNAP-Ed curriculum to help individuals make nutrition-related decisions.
Additional questions from the presurvey included how Food Talk participants may perceive these recipes based on the peer educator’s experience with participants and the likelihood of participants preparing the recipes at home. After preparing the recipe, the postsurvey evaluated similar questions after the peer educator had tasted the finished recipe.
The study showed no significant difference in overall liking or preparation acceptance from the presurvey to postsurvey responses. The presurvey responses provided valuable insights into the perceptions surrounding a recipe before preparing and tasting it; additionally, postsurvey comments solicited specific modifications to adapt ingredients to a specific culture, improve the preparation or cooking time, or make the title more descriptive.
“The use of presurvey and postsurvey questions of acceptance toward unfamiliar recipes offers an underexplored method of evaluating recipes in the community nutrition setting. Our research may indicate that an online process can be used to predict recipe performance without formal testing at a central location,” concluded Dr. Cox.

The risk of hearing loss does not come just from loud machinery or other obvious noise. It can also affect people in public environments like theaters and concert halls. Absorbing this excess sound to make public environments safer for hearing and using the unwanted sound waves to create electricity is the aim of a paper published this week in Physics of Fluids, by AIP Publishing.
“According to the Centers for Disease Control and Prevention, an estimated 12.5% of children and adolescents aged 6-19 years and 17% of adults aged 20-69 years have suffered permanent damage to their hearing from excessive exposure to noise,” author Rajendra Prasad P said. “Noise above 70 decibels for a prolonged period of time may start to damage our hearing. We need systems that can mitigate really big sounds.”
In their study, the authors focused on enclosed spaces like theaters and concert halls and built a system of piezoelectric sensors that can be installed in the walls, floors, and ceilings to absorb sound waves and collect their energy. Sound waves from loudspeakers in these enclosed spaces is usually between 60 and 100 decibels, sometimes reaching 120 decibels, Prasad said.
“We classified the sound present in closed environments based on the intensity (decibels) that can potentially cause hearing loss,” Prasad said. “Sound energy absorbed using piezoelectric sensors is processed by our system to convert it into electrical energy. Based on the pattern of energy generation, the output of the system is switched between battery and direct harnessed output.”
To design an optimal system for capturing sound waves in enclosed spaces, the authors used computer simulations to fine-tune variables including the voltage needed to power the main device component, the frequency and intensity of the input sound, and piezoelectric sensors tested in parallel and serial configurations.
“The surprising fact is the output of the design is maximum around certain frequencies that align with the frequency and intensity of the sound used in theaters or auditoriums,” Prasad said. “Our design reduces the vibration of sound each time it reflects from the piezoelectric material and reduces the overall sound intensity of the enclosed space.”
In addition to decreasing the risk of hearing loss, the authors wanted to design an energy system that is good for the environment, using a smart power management feature that adjusts depending on how much sound is coming in. It also uses environmentally friendly materials.
“The piezoelectric material we used is a form of quartz, which is nothing more than a mineral composed of silica,” Prasad said. “It is easily biodegradable and also recyclable.”

A new study led by chemists at the University of Illinois Urbana-Champaign brings fresh insight into the development of semiconductor materials that can do things their traditional silicon counterparts cannot — harness the power of chirality, a non-superimposable mirror image.
Chirality is one of nature’s strategies used to build complexity into structures, with the DNA double helix perhaps being the most recognized example — two molecule chains connected by a molecular “backbone” and twisted to the right.
In nature, chiral molecules, like proteins, funnel electricity very efficiently by selectively transporting electrons of the same spin direction.
Researchers have been working for decades to mimic nature’s chirality in synthetic molecules. A new study, led by chemical and biomolecular chemistry professor Ying Diao, investigates how well various modifications to a non-chiral polymer called DPP-T4 can be used to form chiral helical structures in polymer-based semiconductor materials. Potential applications include solar cells that function like leaves, computers that use quantum states of electrons to compute more efficiently and new imaging techniques that capture three-dimensional information rather than 2D, to name a few.
The study findings are reported in the journal ACS Central Science.
“We started by thinking that making small tweaks to the structure of the DPP-T4 molecule — achieved by adding or changing the atoms connected to the backbone — would alter the torsion, or twist of the structure, and induce chirality,” Diao said. “However, we quickly discovered that things were not that simple.”
Using X-ray scattering and imagining, the team found that their “slight tweaks” caused major changes in the phases of the material.

“What we observed is a sort of Goldilocks effect,” Diao said. “Usually, the molecules assemble like a twisted wire, but suddenly, when we twist the molecule to a critical torsion, they started to assemble into new mesophases in the form of flat plates or sheets. By testing to see how well these structures could bend polarized light — a test for chirality — we were surprised to discover that the sheets can also twist into cohesive chiral structures.”
The team’s findings illuminate the fact that not all polymers will behave similarly when tweaked in an effort to mimic the efficient electron transport in chiral structures. The study reports that it is critical to not overlook the complex mesophase structures formed to discover unknown phases that can lead to optical, electronic and mechanical properties unimagined before.
Diao also is affiliated with materials science and engineering, chemistry, the Materials Research Laboratory and the Beckman Institute for Advanced Science and Technology at Illinois.
The Office of Naval Research, the Air Force Office of Scientific Research, the National Science Foundation and the U.S. Department of Energy supported this research.

A coronavirus uses protein “spikes” to grab and infect cells. Despite their name, those spikes aren’t stiff and pointy. They’re shaped like chicken drumsticks with the meaty part facing out, and the meaty part can tilt every which way on its slender stalk. That ability to tilt, it turns out, affects how successfully the spike can infect a cell.
Now researchers from the Department of Energy’s SLAC National Accelerator Laboratory and Stanford University, along with collaborators at three more universities, have obtained high-resolution images of intact coronavirus spikes on the surfaces of virus particles; identified a tiny hinge surrounded by sugar molecules that allows the spike’s glob-like “crown” to bend on its stalk; and measured how far it can tilt in any direction.
While the study was carried out on a much less dangerous cousin of SARS-CoV-2, the coronavirus that causes COVID-19, it has implications for COVID-19, too, since both viruses bind to the same receptor on a cell’s surface to initiate infection, said Jing Jin, a biologist at Vitalant Research Institute and adjunct assistant professor at the University of California, San Francisco who performed virology experiments for the study.
The results, she said, suggest that disabling the spike’s hinges could be a good way to prevent or treat a wide range of coronavirus infections.
The team also discovered that each coronavirus particle is unique, both in its underlying shape and its display of spikes. Some are spherical, some are not; some bristle with spikes while others are nearly bald.
“The spikes are floppy and move around, and we used a combination of tools to explore all their possible angles and orientations,” said Greg Pintilie, a Stanford scientist who developed detailed 3D models of the virus and its spikes. Seen up close, he said, each spike is different from all the rest, mainly in its direction and degree of tilting.
The research team reported its findings in Nature Communications.

“Since the pandemic started, most studies have looked at the structures of coronavirus spike proteins that were not attached to the virus itself,” said Wah Chiu, a professor at SLAC and Stanford and co-director of the Stanford-SLAC Cryo-EM facilities where the imaging was done. “These are the first images made of the spikes of this strain of coronavirus while they’re still attached to the virus particles.”
SARS-CoV-2’s more benign cousin
The study has roots in the early days of the pandemic, when research at SLAC shut down except for work aimed at understanding, preventing and treating COVID-19 infections.
Because experiments with the actual SARS-CoV-2 virus can only take place in high-level (BSL3) biosafety labs, many scientists chose to work with more benign members of the coronavirus family. Chiu and his colleagues selected human coronavirus NL63 as their subject. It causes up to 10% of human respiratory infections, mainly in children and immunocompromised people, with symptoms ranging from mild coughs and sniffles to bronchitis and croup.
In 2020, Chiu said, the team used cryogenic electron microscopy (cryo-EM) and computational analysis to image the crowns of NL63 spikes with near-atomic resolution.
But because a spike’s stalk is much thinner than its crown, they were not able to get clear, high-resolution images of both at once.

Zooming in on spikes
This study combined information gleaned from a series of experiments to get a much more complete picture.
First, Stanford graduate student David Chmielewski used cryogenic electron tomography (cryo-ET) to combine cryo-EM images of viruses that were taken from different angles into high-resolution 3-D images of more than a hundred NL63 particles.
SLAC senior scientist Michael Schmid plugged those images into a 3D visualization tool and discovered that each of a particle’s spikes was bent in a unique way. Another SLAC scientist, Muyuan Chen, used advanced image reconstruction to create maps showing the average density of the spikes’ crowns and stalks.
Zooming in on one of those spikes, biological chemist Lance Wells at the University of Georgia used a technique called mass spectrometry to pinpoint the site-specific chemical compositions of the 39 sugar chains attached to each of the spike’s three identical proteins.
Finally, Abhishek Singharoy, a computational biophysicist at Arizona State University, and his student, Eric Wilson, integrated all those measurements into atomic models of the spikes’ crowns and stalks at different bending angles, and carried out further simulations to see how far and how freely a spike can bend.
“It turns out that no matter what, the spikes have a preferred bending angle of about 50 degrees,” Chiu said, “and they can tilt up to 80 degrees in any direction in the simulation, which matches well with our cryo-ET experimental observations.”
The bending occurred at a place on the stalk, just below the crown, where a particular cluster of sugar molecules clung to the protein, forming a hinge. Computer simulations suggested that changes in the structure of this hinge would affect its ability to bend, and lab experiments went one step further: They showed that mutations in the protein part of the hinge made the spike much less infectious. This suggests that targeting the hinge could provide an avenue to fight the virus.
“People working on the more dangerous coronaviruses, including MERS-CoV and SARS-CoV-2, have identified a region equivalent to this one and discovered antibodies targeting this region,” Jin said. “That tells us it’s a critical region that is highly conserved, meaning that it has stayed much the same over the course of evolution. So maybe by targeting this region in all coronaviruses, we can come up with a universal therapy or vaccine.”
This work was supported by the National Virtual Biotechnology Laboratory, a group of Department of Energy national laboratories that was focused on responding to the COVID-19 pandemic with funding provided by the Coronavirus CARES Act; the National Science Foundation; and the National Institutes of Health.

For the first time, teachers in a nationwide study have told researchers what strategies they think work best to deal with student violence against educators.
Teachers rated suspending or expelling students as the least effective way of addressing violence, despite the popularity of “zero tolerance” policies in many school districts.
Instead, teachers rated prevention policies, such as counseling for troubled students and improving school climate, as the best strategy for dealing with violence.
“Teachers are the experts on the ground, and our results show that they believe prevention strategies are the ones that really work best in the schools, much more so than excluding kids who get into trouble,” said Andrew Perry, lead author of the study and a postdoctoral scholar in the Department of Educational Studies at The Ohio State University.
The study was published online recently in the journal School Psychology.
Results showed that schools’ use of exclusionary discipline practices — such as expulsion or suspension of students — was linked to a higher likelihood of teachers reporting violence against themselves. That could include verbal attacks and threats, and physical and property violence.
That may be because suspending or expelling students makes them angrier and leads to more violence, said study co-author Eric Anderman, professor of educational psychology at Ohio State.

“Removing the student doesn’t make the school safer in the long run,” Anderman said. “And it certainly doesn’t address the underlying issue of what caused the violent behavior in the first place.”
Data for the study came from a web survey, done in 2020-21, of 4,471 pre-K to 12th grade teachers from across the country.
Teachers reported on whether their school used 21 common safety measures. These measures fit into four categories. Along with exclusionary discipline and prevention measures, the other two categories were school hardening (such as use of metal detectors and security cameras) and crisis intervention (such as using physical restraint during violent episodes).
Teachers also rated their school’s effectiveness at using the 21 safety measures.
Finally, participants rated how often they experienced 13 different types of violence from students in the past year.
Results showed that more than 95% of teachers reported their schools used all four categories of school measures addressing violence.

Teachers rated prevention as the most effective strategy for dealing with violence. Crisis intervention was rated second, school hardening was third and exclusionary practices were rated as least effective.
In general, the more effective teachers thought strategies were at addressing violence, the less violence they reported against themselves, Perry said.
As mentioned earlier, use of exclusionary practices was associated with more reports of violence against teachers. Use of prevention practices and school hardening had no association with teachers’ reports of violence. Use of crisis intervention was associated with a relatively small higher likelihood of violence.
Overall, the results show that the experiences of teachers agrees with previous research showing that suspending and expelling students doesn’t help make schools safer, Anderman said.
That’s concerning because, in some local school board elections, candidates have run on zero-tolerance policies that would make exclusionary policies even more entrenched.
“There are some people who think that the answer to school violence is to get the bad kids out of school, but our data shows that teachers don’t think that works,” Anderman said. “Other research supports that view.”
What does seem to work is prevention policies, Perry said. Offering counseling to students rather than keeping them out of school is one such measure. Another is to improve school climate so that teachers, students and administrators work together to make the school a place where they all want to be.
“These are proactive approaches that schools can use to try to reduce and prevent violent events before they occur,” Perry said.
Anderman said teaching social-emotional skills in school — such as self-awareness, self-control and interpersonal skills — can be an important part of violence prevention, even though some critics want schools to only focus on “reading, writing and arithmetic.”
This preventive approach is similar to that used by public health officials to prevent disease and chronic health issues.
“Public health experts know that it is easier and less costly to pay for a test that can identify a health problem early than to pay for treatment later,” Anderman said. “Schools can take a lesson from that to prevent violence.”
The study was part of the work of the American Psychological Association Task Force on Violence Against Teachers and School Personnel.
Other co-authors on the study came from the Center for Justice Innovation, Rutgers University, DePaul University, University of California, Los Angeles, University of North Carolina at Chapel Hill and the University of California, Berkeley.

A mission to rescue cancer-stricken children from the violence in Gaza has involved multiple countries and last-minute connections in the chaos of war.They are some of the most vulnerable in Gaza.The youngest is not even a year old; the oldest is 14. All are battling lymphoma, leukemia and tumors that doctors said could kill them if left untreated.Over the past 10 days, 21 children with cancer have been evacuated from Gaza to hospitals in Egypt and Jordan, according to doctors involved in the effort. But at least 30 other young cancer patients have not made it out, and aid workers said that in the chaos of war, they can no longer reach some of the families.“This is catastrophic,” said Dr. Bakr Gaoud, the head of Al-Rantisi Specialized Hospital for Children, which was the only medical center with a pediatric cancer ward in Gaza until it was forced to shut down on Friday during heavy fighting. Even before the hospital closed, critically ill patients were being sent home through violent streets or transferred to Al-Shifa, a nearby hospital that is under siege by Israeli forces.Hospitals have become a particular flashpoint in the war as Israel has accused Hamas of turning medical facilities, including Al-Rantisi and Al-Shifa, into safe houses and command centers. Hamas and hospital officials have denied the allegations.The effort to evacuate children with cancer began in mid-October and required negotiations among the White House, Egypt, Israel and Palestinian health officials in Gaza, which is controlled by Hamas.But those involved in the evacuation said it has proceeded fitfully.Aid workers and doctors, who spoke on condition of anonymity because of the sensitivity of the efforts, described frantic families who lost their cell service and missed the specific days when their children had been given permission to cross into Egypt. Some waited for hours for ambulances that never made it to a meeting point.One family arrived at the border only to discover that their child had been approved to cross, but the parent’s name had been inexplicably left off the list.The children’s plight is a microcosm of the suffering in Gaza since the war began just over a month ago, after Hamas launched a surprise assault that Israeli authorities say killed 1,200 people. Israel’s retaliation has killed more than 11,000 people, including more than 4,500 children, according to health officials in Gaza.Most of the children with cancer were being treated at Al-Rantisi, which had 35 inpatient pediatric cancer patients as of two weeks ago, Dr. Gaoud said. But as shells hit the hospital’s water tanks and power system over the past week, it began to empty out.On Friday, Dr. Gaoud said, Al-Rantisi was forced to shut down entirely, with staff members dragging some patients outside in their beds to wait for ambulances. Israeli soldiers provided a map of what they said was a safe route through the fighting.The children were given one last dose of chemotherapy before they left. Without further care, Dr. Gaoud said, “their cases will deteriorate.”The emergency effort to evacuate the patients was organized by the World Health Organization and St. Jude Children’s Research Hospital, which had been involved in building up services at Al-Rantisi.The organizations created a registry of children to be moved, with phone numbers for their relatives. St. Jude’s also promised to organize their transport into Egypt and ensure their medical care.But the names of the children had to be added to a daily list of those approved to pass through the Rafah border crossing into Egypt, which was no simple task. More than two weeks passed with no evacuations.Pediatric cancer patients had to be added to a daily list of people approved to cross the Rafah border crossing into Egypt.Samar Abu Elouf for The New York TimesSt. Jude’s appealed to the White House, which had partnered with the organization on a similar evacuation of pediatric cancer patients in Ukraine. Desperate messages from hospitals were already fueling the Biden administration’s push for humanitarian pauses in the conflict, according to a senior administration official, who spoke on the condition of anonymity to discuss internal White House communications.The official was shown text messages from medical workers in Gaza. One that reached the White House came from an Al-Rantisi nurse.“Never in my life did I think we as a cancer hospital will be under siege with missiles, and phosphorus bombs are everywhere,” the nurse wrote. “I swear I said we need to get our message and voice out. Speak to the White House, to anyone.”“This is enough, stop, this is enough. We are a hospital for kids,” the message said. “Many are taking shelter, and none of them have any weapons or anything. They lift their hands and ask for help. These are sick cancer kids. This is a catastrophe.”U.S. officials have managed to secure passage of some 400 Americans through the Rafah crossing into Egypt since the war began, and they used those same channels to help get the pediatric cancer patients on the list for safe passage, according to a senior administration official.The list of people allowed through the crossing is compiled daily and is coordinated by Egypt, which has taken in the bulk of the evacuees. Israel, which vets the list to ensure that it does not include Hamas fighters, raised no objection to the Americans’ request to make the patients a priority, a senior administration official said.Curtis Ried, the chief of staff for the National Security Council, said President Biden “directed us to do whatever we could to help these kids get out.”“So we’re still hopeful and we’re still pushing every day to see if we can help get these other children out,” Mr. Ried said.On Monday, as Gaza’s health system collapsed by the hour, Mr. Biden said his “hope and expectation is that there will be less intrusive action relative to hospitals” and that the United States had continued to be in contact with Israel on the issue.“So I remain somewhat hopeful, but hospitals must be protected,” he added.The first patient crossed on Nov. 4, followed by eight more two days later, then several more groups for a total of 21 as of Tuesday. The remaining children, whose ages ranged from a few months to 14, have been approved to leave, but it is unclear when or whether they will be able to given the violence in the streets.Most of the children who have not made it out yet are trapped in northern Gaza, where the fighting is raging, a doctor involved in the evacuation said. An aid worker said one family walked 11 hours to make it to the Rafah crossing.The children’s plight is a microcosm of the broader suffering in Gaza since Israel started missile and ground attacks.Yousef Masoud for The New York TimesA 7-year-old girl was among the most dire cases. When the war started, she had just been diagnosed with leukemia, or blood cancer, according to doctors involved in the evacuation effort. She had been scheduled to be taken outside Gaza for care. But she could not be moved because of the violence, and her white blood cell count rose dangerously high.As the fighting intensified, her family fled with her to southern Gaza, looking for safety and shelter. When the girl was approved for evacuation, aid workers were unable to reach her parent for two days because of problems with telephone service.When they finally got in contact, an ambulance was hastily organized to get the girl to the border. But that day, for some reason, no one was allowed to cross. Only in the past few days did the girl make it to Egypt.Dr. Rik Peeperkorn, the W.H.O.’s representative for Gaza and the West Bank, said the evacuation of the children so far is “a small glimmer of hope” in an overwhelming humanitarian crisis. But, he added, “Many more children and adults urgently need medical evacuation outside Gaza. Time is running out for them.”He also said that the breakdown in medical care will mean some children with cancer will not even be diagnosed.At Al-Rantisi, the families of the pediatric cancer patients were a close-knit group, doctors and aid workers say. Some had known one another since their babies were born, and they had comforted one another through diagnoses and treatments. In recent weeks, they took refuge together in their children’s hospital rooms to stay safe from bombardments. They even managed to be happy for their friends who had been called from the evacuation list, even as they agonized over whether their own children ever would be.But now, many are feared “scattered into the streets,” said Steve Sosebee, the founder and president of the Palestine Children’s Relief Fund, which opened the oncology ward at Al-Rantisi in 2019, building up a supply of cancer drugs and a training staff.When the bombardments began, many families decided that they would go the rest of their cancer journey alone. “Some families took it upon themselves to leave, even though they had no place to go and their child had no alternative medical care available to them outside of the department,” Mr. Sosebee said.Al-Rantisi’s young cancer patients had endured conflicts before that had disrupted their treatment. But never such a confluence of risks — including bombings, dehydration and malnutrition, said Dr. Zeena Salman, a pediatric oncologist based in the United States who has worked with patients in Gaza for eight years.“In this case, the stakes are much, much higher for these children,” Dr. Salman said. “The ones who are spared deaths from bombs, certainly these delays in their treatment, put them at higher risk. So, there’s kind of a risk of acute death, or if they survive, the risk of not being able to be cured of their cancer.”Abu Bakr Bashir

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