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Monthly Archives: March 2022
Brain infiltration of breast cancer stem cells is facilitated by paracrine signaling by inhibitor of differentiation 3 to nuclear respiratory factor 1…
Posted: March 25, 2022 at 2:45 am
Abstract: Treatment options for brain metastatic breast cancer is limited because the molecular mechanism for how breast cancer cells infiltrate the brain is not fully understood. In order for breast tumors to metastasize to the brain first cells need to detach from the primary tumor, enter in the blood circulation, survive within the microvascular niche, and then cross the blood brain barrier (BBB) to colonize into the brain. It is critical to understand how breast cancer cells transmigrate through the BBB to prevent brain metastasis. Nuclear respiratory factor 1 (NRF1) transcription factor has been reported to be highly active in several human cancers and its aberrant expression facilitates in the acquisition of breast cancer stem cells (BCSCs). Inhibitor of differentiation protein 3 (ID3), a transcription regulating protein, induces pluripotent endothelial stem cells (ESCs). Herein we investigated if NRF1-induced BCSCs could cross a BBB model and guiding of BCSCs by ID3-induced ESCs across the BBB. BCSCs and ESCs were subjected to functional gain/loss experiments to determine if NRF1/ID3 contributed to lineage specific BCSCs organ entry. First, we tested whether NRF1 promoted migration of breast cancer using a BBB model consisting of BCSCs or MDA-MB231 cells, brain endothelial cell layer, and astrocytes. NRF1 overexpression increased the propensity for BCSCs and NRF1-induced MDA-MB231 cells to adhere to brain endothelial cells and migrate across a human BBB model. Increased adhesion of NRF1 induced BCSCs to ESCsID3 was detected. NRF1 induced BCSCs crossed through the BBB model and this was promoted by ESCsID3. We also showed that environmental relevant exposure to PCBs (PCB153 and PCB77) produced differential effects. Treatment with PCB153 showed increased growth of NRF1 induced BCSCs tumor spheroids and increased in vivo migration of ESCsID3. Exosomal ID3 released from endothelial cells also supported the growth of NRF1 induced BCSCs and provide the basis for paracrine effects by ESCsID3 associated with breast tumors. Xenograft experiments showed that ID3 overexpressing brain ESCs not only supported the growth of BCSC tumorospheroids but guided them to the neural crest in zebrafish. These findings show for the first time a novel role for ID3 and NRF1 by which ESCsID3 help guide BCSCsNRF1 to distant metastatic sites where they most likely facilitate the colonization, survival, and proliferation of BCSCs. This knowledge is important for pre-clinical testing of NRF1/ID3 modifying agents to prevent the spread of breast cancer to the brain.
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Brain infiltration of breast cancer stem cells is facilitated by paracrine signaling by inhibitor of differentiation 3 to nuclear respiratory factor 1...
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Efficacy of hematopoietic stem cell mobilization regimens in patients with hematological malignancies: a systematic review and network meta-analysis…
Posted: March 25, 2022 at 2:45 am
This article was originally published here
Stem Cell Res Ther. 2022 Mar 22;13(1):123. doi: 10.1186/s13287-022-02802-6.
ABSTRACT
BACKGROUND: Efficient mobilization of hematopoietic stem cells (HSCs) from bone marrow niche into circulation is the key to successful collection and transplantation in patients with hematological malignancies. The efficacy of various HSCs mobilization regimens has been widely investigated, but the results are inconsistent.
METHODS: We performed comprehensive databases searching for eligible randomized controlled trials (RCTs) that comparing the efficacy of HSCs mobilization regimens in patients with hematological malignancies. Bayesian network meta-analyses were performed with WinBUGS. Standard dose of granulocyte colony-stimulating factor (G-CSF SD) was chosen as the common comparator. Estimates of relative treatment effects for other regimens were reported as mean differences (MD) or odds ratio (OR) with associated 95% credibility interval (95% CrI). The surface under the cumulative ranking curve (SUCRA) were obtained to present rank probabilities of all included regimens.
RESULTS: Databases searching and study selection identified 44 eligible RCTs, of which the mobilization results are summarized. Then we compared the efficacy of mobilization regimens separately for patients with multiple myeloma (MM) and non-Hodgkin lymphoma (NHL) by including 13 eligible trials for network meta-analysis, involving 638 patients with MM and 592 patients with NHL. For patients with MM, data are pooled from 8 trials for 6 regimens, including G-CSF in standard dose (SD) or reduced dose (RD) combined with cyclophosphamide (CY), intermediate-dose cytarabine (ID-AraC) or plerixafor. The results show that compared with G-CSF SD alone, 3 regimens including ID-AraC + G-CSF SD (MD 14.29, 95% CrI 9.99-18.53; SUCRA 1.00), G-CSF SD + Plerixafor SD (MD 4.15, 95% CrI 2.92-5.39; SUCRA 0.80), and CY + G-CSF RD (MD 1.18, 95% CrI 0.29-2.07; SUCRA 0.60) are associated with significantly increased total number of collected CD34+ cells ( 106/kg), among which ID-AraC + G-CSF SD ranked first with a probability of being best regimen of 100%. Moreover, ID-AraC + G-CSF SD and G-CSF SD + Plerixafor SD are associated with significantly higher successful rate of achieving optimal target (collecting 4-6 106 CD34+ cells/kg). For patients with NHL, data are pooled from 5 trials for 4 regimens, the results show that compared with G-CSF SD alone, G-CSF SD + Plerixafor SD (MD 3.62, 95% CrI 2.86-4.38; SUCRA 0.81) and G-CSF SD plus the new CXC chemokine receptor-4 (CXCR-4) antagonist YF-H-2015005 (MD 3.43, 95% CrI 2.51-4.35; SUCRA 0.69) are associated with significantly higher number of total CD34+ cells collected. These 2 regimens are also associated with significantly higher successful rate of achieving optimal target. There are no significant differences in rate of achieving optimal target between G-CSF SD + Plerixafor SD and G-CSF + YF-H-2015005.
CONCLUSIONS: In conclusion, ID-AraC plus G-CSF is associated with the highest probability of being best mobilization regimen in patients with MM. For patients with NHL, G-CSF in combination with plerixafor or YF-H-2015005 showed similar improvements in HSCs mobilization efficacy. The relative effects of other chemotherapy-based mobilization regimens still require to be determined with further investigations.
PMID:35317856 | DOI:10.1186/s13287-022-02802-6
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The Human Induced Pluripotent Stem Cell Test as an Alternative Method for Embryotoxicity Testing – Newswise
Posted: March 25, 2022 at 2:45 am
Abstract: The evaluation of substances for their potency to induce embryotoxicity is controlled by safety regulations. Test guidelines for reproductive and developmental toxicity rely mainly on animal studies, which make up the majority of animal usage in regulatory toxicology. Therefore, there is an urgent need for alternative in vitro methods to follow the 3R principles. To improve human safety, cell models based on human cells are of great interest to overcome species differences. Here, human induced pluripotent stem cells (hiPSCs) are an ideal cell source as they largely recapitulate embryonic stem cells without bearing ethical concerns and they are able to differentiate into most cell types of the human body. Here, we set up and characterized a fetal bovine serum (FBS)-free hiPSC-based in vitro test method, called the human induced pluripotent stem cell test (hiPS Test), to evaluate the embryotoxic potential of substances. After 10 days in culture, hiPSCs develop into beating cardiomyocytes. As terminal endpoint evaluations, cell viability, qPCR analyses as well as beating frequency and area of beating cardiomyocytes by video analyses are measured. The embryotoxic positive and non-embryotoxic negative controls, 5-Fluorouracil (5-FU) and Penicillin G (PenG), respectively, were correctly assessed in the hiPS Test. More compounds need to be screened in the future for defining the assays applicability domain, which will inform us of the suitability of the hiPS Test for detecting adverse effects of substances on embryonic development.
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Hard Time: Vermont Hasn’t Lost a Single Prisoner to COVID-19. But at What Cost? – Seven Days
Posted: March 25, 2022 at 2:42 am
Before Newport police took Michael Cornell to prison, they brought him to the hospital. The 33-year-old was suspected of stealing $1,184 from a computer repair store and robbing a hotel clerk of $168. Cornell was unemployed at the time, on probation for a domestic assault and, he told police, in need of mental help.
Cornell didn't remember breaking into the computer store, but he acknowledged buying 15 lorazepam, a prescription anxiety medication that can cause memory loss, earlier the same night in January 2021. The hospital developed a safety plan for Cornell because he was homicidal and suicidal, according to police records. Following his release, the cops arrested and lodged him at Northern State Correctional Facility in Newport. A judge would order Cornell to be held without bail.
It was an inauspicious time to be confined inside Vermont's largest prison. Pandemic precautions meant that Cornell's two young children, ages 4 and 7, couldn't visit. The chow hall had been mothballed, so prisoners were forced to eat meals inside their cells, which double as bathrooms and are roughly the size of one. Basketball was banned, and classes were canceled or held over the phone. An overstretched corps of correctional officers tried to maintain calm among units of men who felt increasingly cooped up.
That was on good days. On bad days, when COVID-19 was in the air, the prison went on full lockdown, which meant that prisoners were confined to their cells for up to 23 hours and 45 minutes per day.
At Northern State, one of six prisons in Vermont, there have been a lot of bad days during the past year. A few weeks after Cornell arrived in February 2021, a massive outbreak infected 179 prisoners and kept them locked down for nearly two straight months. Another outbreak, in August, infected 40 people, prompting another lockdown. Then another in November. And fresh infections last month. More lockdown.
During one of those periods, Cornell wrote to Betsy Trucott, the mother of his two children. Cornell told Trucott he was reading books to pass the time while trying to chart a better course for his life.
"I still feel ashamed everyday because of my actions, but I'm also trying not to be too hard on myself so that way I'm not too depressed to make the changes I need to," he wrote in an undated, handwritten letter that Trucott shared with Seven Days. "I wish they had classes to take but fucking covid has stopped everything."
Cornell did not live to endure the most recent outbreak, in February. He died on New Year's Day at age 34, during his 11th month of detention before trial, while housed in a special quarantine cell following an outside medical appointment. The circumstances are still under investigation, but this month the state medical examiner ruled his death an accidental overdose.
The Vermont Department of Corrections remains the only state prison system in the country where the coronavirus has not killed anyone. But Vermont has achieved this distinction through protective measures that shut down most of the rehabilitative aspects of incarceration and intensified the punitive ones, including unprecedented amounts of time confined to cells. The precautions have not prevented outbreaks or relentless lockdown cycles, even after booster shots became available. Some prisoners have spent as much as half of the last four months under full lockdown, a Seven Days analysis found.
The conditions faced by roughly 1,300 Vermont prisoners and many of the 1,000 corrections workers during COVID-19 are difficult for anyone on the outside to comprehend, though few probably spend much time trying. The discomfiting reality is that, even as many other institutions have dropped most onerous precautions nursing homes have allowed visitors for more than a year, for example Vermont prisons have remained sealed off to the loved ones of the incarcerated.
Meanwhile, the pandemic has worsened a critical shortage of correctional officers and interrupted nascent efforts aimed at reforming the long-troubled department, which is now on its third commissioner since 2020. Earlier this year, the situation got so bad at two of the men's prisons that the department took the extraordinary step of locking down inmates not to protect them from COVID-19, but because too few correctional officers were available to safely manage their movement.
Last October, Gov. Phil Scott appointed Nicholas Deml, a former Central Intelligence Agency official and Capitol Hill aide, as the department's new leader, replacing Jim Baker, who stepped in as interim commissioner in 2020 in the wake of a sexual misconduct scandal at the women's prison that Seven Days exposed just before the pandemic hit. The 34-year-old Deml, who has no prior experience in corrections, is now charged with addressing the system's woeful workforce shortage and reforming its toxic culture.
First, he's trying to turn the page on the two-year-long COVID-19 crisis. This month, the department quietly enacted a phased plan that could allow the prisons to resume a semblance of normal operations in the weeks ahead. Each prison will be able to offer in-person family visits, programs, unrestricted recreation and normal dining hall operations, as long as staff and inmates go several weeks without a cluster of uncontained infections.
"I don't want anybody to succumb to this illness," Deml said. "But as we look to the future, I think we also need to weigh the mental and emotional toll and physical toll, frankly, in some instances that this has taken on people."
During the last two weeks of February, COVID-19 swept through Southern State Correctional Facility in Springfield, which meant that Matthew Hathaway watched a lot of TV.
Hathaway, 38, takes his television seriously. He recently threatened a hunger strike, he claimed, to get correctional officers to move him from a cell where the TV didn't get his preferred channels.
On weeknights, right after watching "Jeopardy!," Hathaway would call his fiance using his tablet computer. All Vermont inmates receive tablets through a for-profit contractor, although watching movies or listening to music on it costs money. Emails, too, cost 25 cents each. It's sort of like being locked down with a hotel minibar.
For weeks on end, Hathaway and his tablet were confined to a room that measures eight cinder blocks long by five and a half cinder blocks wide, furnished with a small desk, a twin bed, the TV, some shelves and a toilet. He got only 15 minutes outside the cell each day, generally to use the shower. "If you want to know what it's like to be locked down, lock yourself in your bathroom and stay there for a month," he said.
Lockdowns are the prisons' bluntest COVID-19 safety tool, used to stem outbreaks once testing or contact tracing reveals a widespread exposure. The outbreaks aren't prisoners' fault. The virus generally spreads through staff, who, after work, leave the sterile environment of prison for the unknowns of the outside world then return the next day. By contrast, any time prisoners enter the facility, as a new arrival or after an outside medical appointment, they are sent straight to the quarantine unit often confined to the same cells designed for solitary confinement for two weeks.
Many prisoners are wary of the health risks posed by COVID-19, and 73 percent are vaccinated, slightly more than the 72 percent of facility staff who got their shots. Nearly 700 prisoners have been infected with the virus in Vermont prisons at some point over the last two years, some more than once. Another 185 infections have occurred among Vermont inmates kept at a private prison in Tutwiler, Miss. Of those, only four cases led to hospitalizations. Hathaway is vaccinated but said he didn't see the point in getting a booster shot. He's more concerned about the terms of his confinement.
"I've had basically every right that I have as an inmate violated in the name of COVID," Hathaway said.
Corrections officials can't say how many days each incarcerated person has spent under full lockdown the department doesn't track it. But the available records suggest that between November 11, 2021, and March 11, 2022, Vermont's prisons were locked down nearly one-third of the time, on average. Pairs of inmates were generally locked into cramped concrete cells around the clock and allowed out for just a few minutes to shower. The frequency of these lockdowns varied by location, from 23 days at Chittenden Regional Correctional Facility to 67 at Northern State.
Prisoners have found their own ways to cope. Brielle Barker landed back in prison in the summer of 2020 after she was picked up on a probation violation for a new criminal charge that was later dropped. Barker, who is trans, was taken to Northwest State Correctional Facility in St. Albans. But she petitioned corrections for a transfer to Chittenden Regional, Vermont's only prison for women. Barker stayed there until her release last November.
Inside Chittenden Regional, Barker said, she found ways to keep herself occupied. Yoga and writing workshops were canceled, but she taught herself to crochet, created a series of paintings and advocated for changes to how corrections treats prisoners who are trans.
Barker sometimes got frustrated with corrections officers but said she believed that the department was "trying really hard" to keep COVID-19 at bay. She felt slighted by the reusable microfiber masks that prisoners have been required to wear, which look like camp towels with ear loops and aren't as protective as the KN95s that staff members receive.
When she needed a respite, Barker flipped the mask over her eyes to block out the light. The isolation felt never-ending at times, but she said the pandemic restrictions were more tolerable once she was able to live openly in the women's prison.
"The hardest part was being locked up inside myself and then inside this cage on top of it," she said. "That just wasn't the case once I was in Chittenden, and I was able to be myself."
After 22 days, Hathaway's latest lockdown stint at Southern State ended at 8 a.m. on March 10. The news meant that he could spend several hours each day mingling in his unit's common area, called a dayroom. The 50 or so men in the unit could play cards or use the microwave, but gym time remained limited, and the prison's dining hall was still out of commission.
Hathaway began his morning, he said by phone later that day, by resuming his ritual of walking laps around the dayroom. It's 43 laps to a mile, a figure Hathaway calculated by using printer paper as a ruler to measure the circumference of the room.
As Hathaway described his mathematical accomplishment, a correctional officer wheeled a tray of refried beans, corn, a quesadilla-like entre and a banana to his cell. Hathaway said he wasn't planning to eat, though he wasn't on another hunger strike. He just wants to lose some weight.
Cornell, the inmate who fatally overdosed, had never been imprisoned before his detention last year at Northern State, according to Trucott. It seemed to prompt serious self-reflection.
"He really wanted to try to dig deeper in terms of his own behaviors and psychology," Trucott said.
By last June, Cornell had developed a daily workout regimen and was in "good spirits," a former cellmate recalled in a letter to Seven Days. Motivating Cornell was his desire to be reunited with his kids, whom he couldn't see while locked up.
"I am told by some of his former roommates that he was always talking about them," Trucott said. "That was his big hope."
Among state prison systems during the pandemic, Vermont was one of just four that had yet to allow general family visits in prisons by the time Omicron hit, according to a database maintained by the Marshall Project, a nonprofit news site that focuses on the U.S. criminal justice system. The women's prison at Chittenden Regional was an exception.
Unlike the men's prisons, the women's facility hosts a dedicated program to help children stay connected with their incarcerated mother. Kids-A-Part, operated by the Burlington nonprofit Lund, has for years facilitated one-on-one visits and large group events that help children interact with their mothers in a more communal setting.
Those visits stopped in March 2020, and it wasn't until September 2021 that kids were allowed back, on a limited basis, program coordinator Jess Kell said. Except for lockdown periods, mothers and children can again meet one-on-one for a couple of hours each week in Kell's homey office, appointed with a rocking chair, quilts, art supplies and a basket of My Little Pony action figures.
The meetups are still tricky to arrange, with the uncertainty of COVID-19 an additional barrier for caregivers, who bring kids when school schedules and long travel times allow. Kell said the reunions have been moving to witness and sometimes bear the evidence of 18 months of separation.
At one of the first, Kell recalled a child who "looked at their mom and said, 'I didn't see you the whole time I was 13 years old.'"
Behind bars at Northern State, Cornell also appears to have struggled. He told Trucott he couldn't get mental health treatment because of COVID-19, and he had trouble navigating the close quarters with cellmates. Cornell was also surrounded by drugs. One of the first things he told Trucott by phone, she remembered, was that "all anybody cares about in here is bupe," referring to the medication-assisted therapy for opioid addiction that Vermont law requires prisons to provide.
Cornell had returned from an appointment at the county opioid recovery clinic the day he died, according to Trucott. Northern State medical staff found him just before noon in a cell used to quarantine arriving inmates and began CPR. He was taken to North Country Hospital, where he was pronounced dead.
A medical examiner's review of drugs in Cornell's system detected an array of medications, including the opioid treatment methadone, antidepressants and a prescription sedative. Not all of them had been prescribed to him.
"We're dealing with it the best we can," Trucott said of Cornell's death, "but it's an injustice."
Cornell wasn't the first prisoner to die in one of Vermont's COVID-19 quarantine units. In December 2020, a 36-year-old man at Northeast Correctional Complex in St. Johnsbury hanged himself with a bedsheet four days after being detained on a burglary charge. Another man attempted suicide at Northern State that same year.
It's not clear yet whether lapses at the prison contributed to Cornell's fatal overdose. (Deml, the commissioner, declined to comment, citing the ongoing investigation.) But prisoners' rights advocates have been especially concerned about how the pressures of the pandemic are affecting people with substance-use disorders.
Those who were incarcerated during the pandemic seem to be at an elevated risk to misuse, said Ashley Messier, who founded the prison abolitionist organization Women's Justice & Freedom Initiative after she served prison time at Chittenden Regional. Yet she contends that Vermont has not made adequate investments in programs that help prisoners prepare for their release and to reintegrate once they're out.
"People who struggled with substance-use disorder and mental health have been hit hard by the pandemic. Then pile on having been incarcerated and completely isolated," she said. "Imagine how that compounds the issues."
Early in the pandemic, the Department of Corrections created an emergency policy that required employees from anywhere in the agency to work inside a prison if needed. The fear was that the virus could sweep through prisons, like nursing homes, with scores of staff out sick.
To Georgie Stapleton, a 62-year-old probation officer in the Barre office, the chance that she'd be called in seemed remote. She wasn't even instructed to take a refresher training to prepare her for such an assignment.
Then, on a Friday in January, the order came. She would need to work a 12-hour shift the next day inside a facility that was on full lockdown. Stapleton panicked. "I'm not security minded. I don't think like that," she said. "I'm a therapist."
She called her manager, who, Stapleton said, told her she'd be disciplined if she refused the assignment. Luckily, someone else volunteered, she said. But Stapleton was stunned that her department was conscripting employees she felt were ill-equipped to work as correctional officers.
The episode is one symptom of a public agency run ragged. Corrections, the second-largest department in state government, with 1,048 positions, has recorded more than 450 COVID-19 infections among its employees. Overtime hours soared as the department struggled to attract people willing and able to work in an increasingly intimidating environment.
And those already working there were heading for the exits: Between July 2020 and July 2021, nearly half of all entry-level correctional officers quit, Department of Human Resources data show. The wave of departures was significantly larger than the pre-pandemic turnover rate of 30 percent.
Chad Richardson, a booking officer at Northwest State Correctional Facility in St. Albans, ostensibly works eight hours a day, Tuesday through Saturday. During the worst stretches of the pandemic, however, his shifts lengthened to 12 or 16 hours. He might work 2 a.m. to 2 p.m., or 6 a.m. to 10 p.m., "and then you're back the next morning," he explained to a Seven Days reporter during a guided prison tour earlier this month.
They aren't easy hours, either. The last two years have seen near-constant adjustments to safety protocols. Officers have attempted to police social distancing inside buildings that have been designed to confine.
For those who run programs for prisoners, demand is up and the ability to provide them is hampered. Correctional educator Ritalea Sweeny, for instance, typically would teach high school courses in an on-site classroom. Instead, she's had to teach by phone. Explaining mathematics that way, she said, has been "really difficult."
Not everything about prison work has gotten harder. With fewer prisoners who don't move around as much, there haven't been as many interactions to oversee. The added overtime brings welcome extra cash. But the long hours and stress have strained many officers' personal lives.
The state workers' union and Gov. Scott cut a deal last year to award over $6 million in recruitment and retention bonuses of up to $2,500 for corrections staff. The program was set to expire this month, but the union and the department extended a slightly different version of it through June. Scott signed a bill earlier this month that includes funds for retention bonuses in the upcoming fiscal year.
Deml, the new commissioner, said the department will reevaluate the strategies as June approaches.
"We know that staff really put it all on the line over the last couple of years, and they deserve just compensation for that," he said.
The labor problems in corrections are not a pandemic phenomenon; they've just gotten worse. An annual state Department of Human Resources survey last year found that just 10 percent of corrections employees believed that department morale was "good," down from 22 percent in 2019.
The situation makes the prisons less safe. There's a shared perception that the black market among inmates for medications, a problem known as drug diversion, has gotten worse. The illicit trade includes doses from Vermont's medication-assisted therapy program, which has unwittingly turned the state into a "major drug supplier" behind bars, said Steve Howard, president of the Vermont State Employees' Association, the union that includes corrections workers. The problem, in his view, is that corrections doesn't have enough staff members on the ground to properly administer the medicine. His members view it as a "complete disaster," Howard said.
Deml said COVID-19 protocols that keep staff distanced from prisoners, not a lack of staff, have made stamping out the practice more difficult. Hathaway, from the vantage point of his cell, said he thinks correctional officers have simply turned a blind eye.
The drugs' relaxing effects, he said, make their jobs easier.
"There's no crying in corrections" was something of a catchphrase when Cindy Lack started her career 33 years ago. Now she's trying to change that.
A probation officer, Lack heads a 26-member group of employees who offer peer support to coworkers who need a listening ear.
The stress that correctional officers face can be hard for others to understand, Lack said. Most people don't know what it's like to cut down a man from a bedsheet, or how hundreds of hours inside a prison change the way you move through the outside world. Department veterans get it.
"We need to take care of our staff, or we're not going to have any," Lack said. "We need to take care of what's left."
The essentially volunteer peer support team has existed for years. But during the pandemic, the department made it so that employees no longer needed to seek out help now it's offered to them. Lack's team had fewer than 800 interactions with employees in 2019, she said. The total shot up to 3,200 in 2020 and more than 3,500 last year.
"Folks have found it helpful to talk about what's going on," she said.
VSEA's Howard said the working conditions endured by corrections employees during the pandemic and their accomplishments have been underappreciated. Many of his members feel like they've been fighting a hidden battle, one that even state leaders haven't acknowledged. The governor stopped by the Vermont Correctional Academy last August, his office said, but Howard thinks Scott should do more.
"This is the only corrections department in America that didn't have a death due to COVID," he said. "And the governor hasn't shown up in a single facility to say, 'Thank you.'"
In St. Albans, staff at Northwest State who spoke to Seven Days were finding some reasons for optimism. Their facility had spent fewer days on lockdown during the recent Omicron wave than the other men's prisons. Sweeny, the teacher, was recently able to begin one-on-one tutoring sessions in person, and Richardson said required overtime hours have begun to decrease.
Matt Engels, a shift supervisor who oversees recruitment at the St. Albans prison, keeps a whiteboard on a wall in his office that's otherwise papered with posters of the Green Bay Packers and classic rock bands. The whiteboard showed a flowchart of new hires, including two who were joining up and two more who were slated for interviews.
In the bottom corner, Engels, a 14-year corrections veteran, keeps a running tally of how many officers he's been able to hire and retain since last June. It's up to 22.
"We're not where we want to be, but we're getting where we need to be," he said.
Still, he's cautious about the months ahead, particularly as the department drops more COVID-19 restrictions. Many on Engels' team started working in corrections during the pandemic. They've never had to manage a full chow hall or a visitation room.
For them, the last two years are just the way things are.
No department in state government has more vacant positions than corrections. According to the new commissioner, the 181 openings as of late February are concentrated among correctional officers and other roles inside the prisons. Nearly a quarter of these 500-plus "security" positions, as they're dubbed, are unfilled.
The number of officers working in corrections today remains lower than it was a year ago, Deml conceded in an interview last week. The department has relied on changes to its staffing patterns for instance, by moving to 12-hour shifts in some prisons to reduce total shift changes to prevent more staffing-induced lockdowns such as the ones that happened in recent months. Since then, he said, the recruitment and retention efforts have improved.
Creating a more stable workforce is Deml's unequivocal priority in the months ahead.
"We just came out of a really traumatic event or, we're trying to come out of a very traumatic event in COVID," he said. "And so I think it's a great time for the department to really connect and respect our staff on a human level and make really important investments in them as people."
Deml strikes a softer tone than his predecessor, interim commissioner Baker, who was widely respected and also, as a state official put it, "one tough bastard." Trained as a lawyer, Deml won't say much about his nearly eight years working in classified operations for the CIA.
But he speaks frankly about why he pursued the corrections post. The commissioner didn't want to live part time in Washington, D.C.; he wanted his life to be in Vermont, where his wife lived in their house with their infant daughter. And he saw in corrections an avenue to "really make an impact on human life."
Deml's ideas for turning around the department revolve around making it a more humane place. He's focused on staff wellness, improving professional development opportunities and making sure promotions are based on merit, not an "old boys' network."
"I want to offer that type of just the joy and pleasure and self-worth that somebody gets out of having a career they can be really proud of," he said.
What Deml hasn't emphasized, so far, is funding. To VSEA's Howard, that's a problem. For months, the union has said it will take a substantial taxpayer investment, on the order of $15 million to $20 million per year, to address the chronic staffing problems inside corrections.
Deml doesn't rule out targeted proposals for more resources but said he believes that the $174 million budget the governor endorsed for fiscal year 2023 is enough for corrections leaders to make "really meaningful change for our staff."
There's no doubt that shedding pandemic restrictions inside the prisons will also help. It's not without risks, though. If another COVID-19 wave brought fresh outbreaks in the prisons, they would still move into lockdown, and prisoners would again shoulder the burden. Deml said the department is looking to use narrower, focused lockdowns when possible, such as when only one or two units have active cases.
That's because the most important thing corrections can do right now, Deml said, is try to restore the things that make prison a little more bearable.
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Hard Time: Vermont Hasn't Lost a Single Prisoner to COVID-19. But at What Cost? - Seven Days
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AACR Presents Awards to Further Diversity, Equity, and Inclusion in Cancer Research to Escobar-Hoyos Lab – Yale School of Medicine
Posted: March 25, 2022 at 2:37 am
The American Association for Cancer Research (AACR) has presented two awards to further diversity, equity, and inclusion in cancer research to the Escobar-Hoyos Lab, under the direction of Luisa Escobar-Hoyos, MSc, PhD.
Dr. Escobar-Hoyos is the 2022 recipient of an AACR Career Development Award. The AACR Career Development Award is intended to further diversity, equity, and inclusion in Cancer Research and has been established to support the development of highly talented cancer researchers from under-represented groups. The Escobar-Hoyos laboratory recently discovered that pancreatic cancers are exquisitely susceptible to a range of therapies directed at RNA splicing. Dr. Escobar-Hoyos will use the AACR award to continue her research and specifically to characterize the role of RNA splicing factor mutations in pancreatic cancer pathogenesis and treatment response. These results will uncover a fundamental, yet novel non-mutational mechanism required for pancreatic cancer pathogenesis and tumor maintenance:altered RNA splicing.
A postdoctoral associate in the Escobar-Hoyos laboratory, Natasha Pinto Medici, PhD, is the recipient of a 2022 AACR Career Development Award to further diversity, equity, and inclusion in cancer research. Originally from Brazil, Dr. Pinto Medici obtained her undergraduate and masters degrees in immunology from Universidad Federal do Rio de Janeiro. After being awarded with a competitive Brazilian fellowship for studies abroad, she came to the USA and obtained her PhD in molecular genetics and microbiology from Stony Brook University. Currently she researches the molecular regulation of immunity in pancreatic cancer in the Escobar-Hoyos laboratory.
Submitted by Renee Gaudette on March 24, 2022
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AACR Presents Awards to Further Diversity, Equity, and Inclusion in Cancer Research to Escobar-Hoyos Lab - Yale School of Medicine
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Bioinformatics jobs: All of your options – ZDNet
Posted: March 25, 2022 at 2:37 am
Bioinformatics jobs involve analyzing and interpreting biology-related data. These professionals' work benefits hospitals and medical clinics, healthcare and pharmaceutical companies, biotechnology firms, and research institutions.
As a bioinformatics professional, you're equipped to design and develop the tools, methods, and systems to work with data. Bioinformaticians aid life-saving medicine development, study genes, improve crop productivity, and more.
Bioinformatics professionals work full-time in labs, offices, and research settings. They use statistics, programming, data management, and machine learning skills. They also understand biology and may specialize in a subdiscipline, like genomics or molecular biology.
The federal government, private corporations, and the public sector all employ bioinformatic professionals to analyze and interpret biological data. They also hire individuals who can create software and hardware to manage and assess large datasets.
Bioinformatics jobs may allow you to work remotely, depending on the position and employer.
According to Payscale, the average base salary in informatics is $87,000 per year as of March 2022. Education level, experience, industry, and location influence pay.
You can find top-paying bioinformatics jobs in companies and agencies focused on biotechnological research. Research scientists took home average salaries above $91,000 in 2021. Senior research scientists in biotechnology earned nearly $110,000 on average in early 2022.
Additional education and training prepare you for advanced and managerial bioinformatics positions and may boost your earning potential. Certificates and advanced degrees, such as a computer science master's degree, increase your knowledge.
By gaining insight into emerging technologies through continued education, you position yourself to grow in the field.
Earning a bioinformatics degree may lead to a job in agriculture and wildlife, computer technology, research, or biotechnology.
Bioinformatics jobs are varied and may be highly specialized. You'll find some of the more prominent jobs below.
Bioinformatics jobs in agriculture, zoology, microbiology, and wildlife biology involve assessing data related to plants, crops, and animal health.
You apply knowledge of statistics, computer science, and information technology at companies or in the public sector.
Bioinformaticians in these fields protect and study living organisms, optimizing interactions among them. Depending on the setting, you may work to increase food production, assess genetic variations, or improve land productivity.
Some roles include:
Bioinformatics jobs in computer and data science put your computational and analytical skills to work. In this discipline, you design new hardware and software to assess biological data.
Research and development, technology firms, and healthcare informatics companies may hire bioinformatics specialists to create proprietary software. You may also qualify to work as a biological data scientist in industrial settings.
Common jobs include:
Bioinformatics professionals in pharmaceuticals serve a vital role in the creation, development, and testing of new medications. Bioinformaticians in biotechnology might assess data needed to develop gene therapies and advance immunology.
You may improve existing processes and technologies and establish new data analysis methods. In both pharma and biotech roles, you work alongside fellow scientists and computational biologists to contribute to the field at theoretical and practical levels.
Pharma and biotech roles include:
Clinical bioinformatics data analyst
Project manager for bioinformatics
Human genetics bioinformatics scientist
Public-sector bioinformaticians may work for federal, state, and local governments to address public health and safety issues. The government also employs bioinformaticians in agriculture and wildlife-related roles.
In public sector roles, you may work to improve your environment and the world. Public sector bioinformatics positions also advance military medicine, inform national and regional policies, and contribute to agricultural production.
Job options include:
Bioinformatics scientist with the National Institute of Health
Bioinformatics analyst with a state hospital system
Computational biologist with a local or state department of public health
Research and academic bioinformatics jobs extend from the lab to the classroom. Colleges and universities may employ bioinformatics researchers in labs and as instructors.
Bioinformaticians at colleges and universities often work with public agencies and private companies. Through grants and collaboration, bioinformatics researchers and academics work with funders to tackle projects. For example, you might map the genes that cause a poorly understood disease.
Roles include:
Bioinformatics blends science and technology. You may find jobs in the private and public sectors with a bioinformatics degree.
Bioinformatics jobs involve interpreting data to address vital issues. Sound rewarding? If so, bioinformatics might be the right field for you.
Nicole Galan is a registered nurse who started in a general medical/surgical care unit and then moved into infertility care, where she worked for almost 10 years. She has also worked for over 13 years as a freelance writer, specializing in consumer health sites and educational materials for nursing students. Galan currently works as a full-time freelancer and recently earned her master's degree in nursing education from Capella University.
Nicole Galan is a paid member of the Red Ventures Education freelance review network.
Last reviewed March 22, 2022. Unless otherwise noted, salary data is drawn from Payscale as of March 24, 2022.
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New research sheds light on causes of reproductive disorders, infertility, miscarriage, birth defects – EurekAlert
Posted: March 25, 2022 at 2:37 am
image:Testis tissue section from a wild-type mouse stained for meiotic markers (in pink and green) and DNA (in blue). view more
Credit: Courtesy of Devanshi Jain
Researchers at Rutgers University, Memorial Sloan Kettering Cancer Center, Rockefeller University, and Cornell University are teaming up to examine how the processes that regulate gene expression and chromosome behaviors can lead to health issues, including cancer, birth defects, miscarriage, and infertility.
Cells undergo a remarkable transformation process to form eggs and sperm, which upon fertilization can form an entire organism. A key step of this transformation involves meiosis, a cell division that halves the genome content of cells. During early stages of egg and sperm development, cells divide by mitosis, the process used by most cells in our body. They then undergo a complete remodeling of the gene expression landscape, and switch to meiosis. Mis-regulation of the mitosis-to-meiosis switch can lead to tumor-like growth, depletion of the reproductive cell pool or failure to complete meiosis.
In the new Rutgers-led study in the journal Genes & Development, the researchers applied powerful methods for mapping genome-wide protein-RNA interactions and innovative genetic mouse mutants to define how the RNA helicase, YTHDC2, binds RNA and controls gene expression to regulate meiosis. YTHDC2 and its interacting protein partners form an essential pathway that controls the mitosis-to-meiosis switch. Prior to this study, little was known about the mechanisms regulating this switch in mammals.
Our work sheds light on the genetic and molecular mechanisms that are required for normal meiosis, which is an essential step towards understanding how and why these processes go wrong and lead to reproductive disorders, said Devanshi Jain, a principal investigator of the study and an Assistant Professor of Genetics at the School of Arts and Sciences (SAS) at Rutgers University-New Brunswick. Additionally, as YTHDC2 has been implicated in multiple diseases, especially cancers, our work will have broad implications on those fields as well.
Jain said this new study, along with ongoing research at the Rutgers-housed Jain Lab, explores the genetic and molecular mechanisms of meiosis, and the processes that regulate gene expression and chromosome behaviors. Researchers at the Jain Lab use the mouse model system to explore these fundamental aspects of cell biology.
Understanding meiosis is of paramount importance to reproductive health as errors in meiosis can lead to reproductive cell death and infertility, said Jain. Going forward, we plan to delve deeper into the molecular mechanisms of the YTHDC2 pathway and its control of gene expression. We also continue to study other fundamental aspects of how meiosis is regulated.
Genes & Development
YTHDC2 control of gametogenesis requires helicase activity but not m6A binding
20-Jan-2022
Disclaimer: AAAS and EurekAlert! are not responsible for the accuracy of news releases posted to EurekAlert! by contributing institutions or for the use of any information through the EurekAlert system.
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New research sheds light on causes of reproductive disorders, infertility, miscarriage, birth defects - EurekAlert
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RNA map of cell nucleus reveals new insights into gene regulation and cell division – University of Toronto
Posted: March 25, 2022 at 2:37 am
Most people are familiar with the cell nucleus from grade school biology as a storage compartment for DNA. But the nucleus also contains several distinct structurescalled nuclear bodies or domains and some of them are brimming with genes messages, also known as RNA transcripts.
Scientists are just now beginning to understand these structures, with University of Toronto researchers recently reportingthe first large-scale survey of RNA transcripts that are associated with different nuclear bodies in human cells.
The work, published in the journalMolecular Cell, suggests that the structures act as hubs to co-ordinate gene regulation and cell division.
It was known that some nuclear domains contain RNA, but the composition of that RNA was not systematically probed in previous studies, saidBenjamin Blencowe, senior author on the study and a professor of molecular genetics in the Donnelly Centre for Cellular and Biomolecular Researchat the Temerty Faculty of Medicine.
Our data has shed light not only on the RNA composition of different nuclear domains, but also provides clues as to the functions of some of these domains.
Until now, the information on nuclear body composition has trickled in piecemeal because there were no methods enabling a systematic survey of RNA localized to these structures. But post-doctoral researcher Rasim Barutcuand graduate studentMingkun Wurealized they could apply a method called APEX-Seq, which had been developed by scientists at Stanford University and the University of California, Berkeley.
APEX is an enzyme that can be fused to any protein of interest and allows labeling of RNAsand other biomoleculesin its proximity. The labeled RNAs can then be isolated and identified by sequencing. By fusing APEX to various marker proteins residing in the different nuclear bodies, Barutcu and Wu were able to create RNA maps for each.
The pair collaborated withUlrich Braunschweig, a senior research associate in Blencowes lab, and with the groups of:Anne-Claude Gingras, a senior scientist at the Lunenfeld-Tanenbaum Research Institute,Sinai Health System, and professor of molecular genetics;Philipp Maass, a scientist at TheHospital for Sick Children andassistant professor of molecular genetics;andRobert Weatheritt,a principal investigator at theGarvan Institute of Medical Research inAustralia.
The team discovered swaths of novel RNAs from several hundred to thousands across the nuclear bodies. Previously, only a handful of transcripts were known to be associated with some of these structures, said Barutcu, whose research was supported by the Banting Postdoctoral Fellowship and a fellowship from the Canadian Institutes of Health Research (CIHR).
One piece of data immediately struck the researchers: The nuclear bodies known as speckles were associated with surprisingly high numbers of RNA transcripts with retained introns segments that do not code for proteins. When a gene is transcribed into RNA, introns must be spliced out in the nucleus before the transcript can be released into the cells interior to serve as a template for making proteins.
The finding led them to realize that speckles are associated with a class of introns with delayed splicing. The nature of the transcripts provided a clue to their function. They were transcribed from genes that control various aspects of gene regulation and the cell division cycle. Genes controlling cell cycle progression must be activated in a timely manner so that their protein products are made only when they are needed. Errors in this process are well known drivers of cancer.
The researchers came up with a model in which the role of the speckles might be to co-ordinate intron removal from transcripts in order to regulate their release from the nucleus, and their subsequent translation into protein factors required for gene regulation and the cell cycle. This mechanism would help ensure a rapid response to cellular signals to make the right kinds of proteins at the right time.
Furthermore, when speckles were disrupted, this altered the splicing of the retained introns, including those located in genes that are directly involved in control of the cell cycle, supporting the idea that the speckles are linked to cell cycle progression.
The model opens up new ways of thinking about cell cycle regulation with implications for cancer research, said Blencowe, who holds a Canada Research Chair in RNA Biology and Genomics and Banbury Chair in Medical Research.
Weve uncovered a mechanism involving differential intron retention linked to speckle integrity that could play an important role in not just normal cell division but also how it goes wrong in cancers, he said, noting that the project was made possible by the now defunct CIHR Foundation grant scheme, which provided long-term research funding.
In addition to the speckles, the team also found large numbers of intron-retained transcripts associated with the nuclear lamina, which forms at the periphery of the nucleus. However,the functional significance of this observation remains unclear.
The researchers said they hope others in the field will take advantage of their datasets and open new avenues of research into nuclear body function where many questions remain.
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The Changing Treatment Landscape and the Role of Surgery in RCC – Cancer Network
Posted: March 25, 2022 at 2:37 am
Gennady Bratslavsky, MD, spoke about the evolution for treatments in renal cell carcinoma and how surgery may play a role.
The role of surgery for renal cell carcinoma (RCC) and strategies used for treatment are ever evolving. As options for systemic therapies continually improve, many clinicians are opting to spare patients from undergoing procedures.
Gennady Bratslavsky, MD, professor and chair of the Department of Urology and director of the Prostate Cancer Program at Upstate Medical University in Syracuse, New York, recently hosted a presentation on the role of surgical in management in RCC at the 15th Annual Interdisciplinary Prostate Cancer Congress and Other Genitourinary Malignancies, hosted by Physicians Education Resource, LLC (PER).
I still think that there will be appropriately selected patients [for whom] surgery will remain the first and potentially the main type of treatment. We may even include metastasectomy [for some as] that has been used for years, said Bratslavsky.
In an interview with CancerNetwork, Bratslavsky spoke about what role surgery currently plays in RCC, new strategies on the horizon, and trials he is most excited to see read out.
This is an evolving landscape. We are going to try to operate less on patients who we can avoid surgery, were going to try to prognosticate better and see who can be spared. The term intervention-free survival is something that will hopefully be used more and more. Some trials are being designed, for example, in a role for renal biopsy where type of surgery or timing of surgery may be affected.
The role of surgery for more advanced disease is also ever changing. Obviously, the dogma that every metastatic kidney cancer can be removed is wrong, [but] his can still render patients disease free and offer a durable long-term survival.
The adjuvant [therapy] space is finally having some promise with the recently published KEYNOTE-564 trial [NCT03142334]. Adjuvant pembrolizumab [Keytruda] certainly [provides] an opportunity for us to expect and hope for disease-free survival [DFS]. Most of the adjuvant trials to date have not been more successful [than KEYNOTE-564]. Even in the S-TRAC [NCT00375674] trial of adjuvant [sunitnib; Sutent] utilization for a year after nephrectomy in patients with the kidney cancer that were found to be high risk, the presence of DFS never translated into overall survival [OS].
While KEYNOTE-564 is yet to matureto demonstrate whether its use in the adjuvant setting would help with OS is yet to be determinedthere is certainly quite a bit of hope that after 2 years of follow up, were starting to see a promise and a strong signal that this DFS may translate into OS, although this has yet to be seen. The recently completed PROSPER trial [NCT03055013] is bringing another opportunity for us to evaluate the role of immunotherapy in the neoadjuvant as well as the adjuvant setting for high-risk patients. There are many unanswered questions. Even if we identify an agent that is effective in improving DFS, we will always question the patients who would have not recurred and still would be subjected to therapy. There is still an ongoing need for better identification of these patients that are most likely to recur beyond our standard clinical variables that have been traditionally used in designing the trials for both neoadjuvant and an adjuvant therapy.
Any research [conducted] has an enormous impact [on] the molecular subcategorization of renal neoplasms, the understanding of genetics, branched evolution, our ability to detect the circulating tumor DNA, and the numerous structures that still contain many of the genetic material and prognostic information. All of this has an enormous potential [for clinical impact].
Were continuously learning about new pathways that may bring in more systemic options, with the biggest breakthrough [being] in our continued appreciation of how heterogeneous kidney cancer is as a disease, how heterogeneous the molecular characteristics are, and how heterogeneous the clinical course and the metastatic potential of each tumor is. These are not tumors that are created equal. They possess very different clinical behaviors and opportunities for targeted or immunotherapies. Research is strong.
Our lab at SUNY Upstate Medical University focuses on the role of molecular chaperones in identification of potential targets and how activity of chaperones can be modified. Our lab has been creating new avenues for therapeutics. Numerous centers and laboratories are doing a great job in identifying these new avenues into how this cancer can be targeted or identified, and even the identification of some biomarkers for better disease response. [There are many paths] that were trying to tackle from different angles.
Choueiri TK, Tomczak P, Park SH, et al. Adjuvant pembrolizumab after nephrectomy in renal-cell carcinoma. N Engl J Med. 2021;385(8):683-694. doi:10.1056/NEJMoa2106391
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The Changing Treatment Landscape and the Role of Surgery in RCC - Cancer Network
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Research Associate, Crop Genomics job with UNIVERSITY OF WESTERN AUSTRALIA | 286656 – Times Higher Education
Posted: March 25, 2022 at 2:37 am
The School of Biological Sciences
Batley Lab Crop Genomics
About the team
The School of Biological Sciences is a large, multidisciplinary School with over 80 high-calibre staff delivering world-class education and research programs to approximately 600 undergraduate and postgraduate coursework students and is responsible for the supervision of ~100 PhD students. The School is research-intensive with expertise in the disciplines of Computational Biology, Ecology & Conservation, Evolutionary Biology, Neuroscience and Science Communication.
The Batley lab studies genetics and genomics on a range of crop and pathogen species, including subterranean clover, soybean, wheat, banana and chickpea, with other projects on a wide range of species including parasitic plants and pearl oyster, however our primary research focus is on the agricultural oilseed crop Brassica napus (canola), and its interactions with the disease-causing fungus Leptosphaeria maculans (blackleg).
Related research projects include identification of blackleg disease resistance genes in canola using next-generation sequencing and high-throughput molecular marker approaches. New projects are investigating the role of structural variation in the Brassica genomes, specifically in relation to disease resistance and understanding the evolution of disease resistance genes. In conjunction with this our lab continues to work on development of genomes and pan genomes.
About the role
You, as the successful appointee, will be responsible for research projects investigating plant pathogen interactions and evolution of disease resistance genes and preparing and publishing scientific publications with a focus on crop plants.
You will also be involved in project planning, execution of molecular experiments, data analysis and interpretation, preparation of scientific manuscripts for publication and participation in the supervision of other research personnel engaged in the projects.
To be considered for this role, you will demonstrate:
Full details of the position's responsibilities and the selection criteria are outlined in the position description.
Closing date:Friday, 20 May 2022
This position is open to international applicants.
Application Details: Please apply online via the Apply Now button.
Our commitment to inclusion and diversity
UWA is committed to a diverse workforce. We celebrate inclusion and diversity and believe gender equity is fundamental to achieving our goal of being a top 50 university by 2050.
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Research Associate, Crop Genomics job with UNIVERSITY OF WESTERN AUSTRALIA | 286656 - Times Higher Education
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