Monthly Archives

January 2019

BODY LOTION

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Lord Jones Pain and Wellness Pure CBD Body Lotion, $50

Lord Jones is known for their killer packaging and potent THC gummies (which, speaking from experience, holy wow), but their lotion deserves a cult-following of its own. Touted as an anti-inflammatory sunburn soother, I coated my sore, rosy shoulders with it after an August afternoon sans sunscreen (I forgot, so judge me), and while I wouldn’t say it made my burn dissipate faster—sorry, only time can do that—my skin did feel significantly less tender, to the point where I could slide on tight bra straps without feeling that intense post-burn stinging. Basically, I’m keeping this on hand for literally anytime my skin feels itchy, sore, or irritated, which, thanks to the impending winter, will be often.

Overall, I wouldn’t say that CBD beauty products changed my life, but they definitely made my routine more fun, and way more soothing. To feel legitimate pain-soothing effects without downing Advil or slathering on Bengay was kind of awesome, especially when you realize there are practically zero downsides.

LIP BALM

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Jersey Shore Cosmetics Super Sativa Medicinal Hydrating Balm, $15

My lips are chronically dry, so this was an easy addition to my collection of balms and masks. Each layer I swiped on brought with it a dreamy whiff of rosemary and cannabis that skewed sweet and earthy, rather than skunky. The formula, made extra-hydrating by sunflower seed and lavender oils, can work to soften dry patches pretty much anywhere you rub it on, since “CBD enhances your skin’s lipid bilayer, so it could help prevent dryness and provide a good barrier against moisture loss,” says Dr. Imahiyerobo-Ip. And thanks to CBD’s inherent anti-inflammatory properties, my lips were left soft and smooth with no signs of chapping or flaking, which is a major departure from my normal M.O.

FACIAL SERUM

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From Ever Since Contour Serum, $95

This silky anti-aging serum is infused with green tea extract and chamomile, plus a dose of cannabinoid oil, formulated to smooth itty bitty fine lines and tighten saggy, puffy skin. Seeing as those are already two incredibly large claims to make, especially for a product that doesn’t contain retinoids, I was genuinely surprised to see that my cheeks and jaw did appear slightly tighter after a few weeks of massaging this on every night, which is an improvement that’s more than welcome on a Monday morning. Of course, because it’s impossible to know the potency of CBD oil, it’s tough to say whether or not CBD is the hero ingredient in this serum, but I’m not complaining either way.

EYE SERUM

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CBD For Life Eye Serum, $32

This lightweight serum claims reduce dark circles and puffiness, and, according to Dr. Imahiyerobo-Ip, CBD may even have preventative anti-aging benefits when it comes to the ever-sensitive eye area: “Cannabis is filled with antioxidants, like vitamin A, vitamin D, and vitamin E, all of which will be helpful in preventing damage and premature crepe-iness under your eyes,” she says. So I dabbed on a pea-sized drop of serum in the morning, pre-concealer, and again before bed for about a week, and actually did notice a slightly plumper, smoother eye area—as if I’d just had a really excellent facial and a few years shaved off my face.

BATH SALTS

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Ambika Herbals CBD Bath Salts, $30

College cheerleading left me with a slipped spinal disc that still, to this day, sends shooting pain down my legs. So after a particularly achy day, I sprinkled the suggested amount of salts into a hot bath and submerged myself, expecting nothing more than a blah, Epsom-salt effect. But I stood CORRECTED. Within 15 minutes, the tightness in my lower back had melted substantially, and the pain in my calves completely disappeared. Oh, and did I mention the glorious cloud of chamomile and lavender-scented steam filling the air?

After an entire hour, I was Benjamin Button-levels of pruned and completely blissed out, because my intense pain was actually gone. The effects lasted throughout the rest of the night, and even if studies haven’t yet proven that CBD soothes deep-tissue pain, you’ll still find me floating in this weed-like magic every Sunday until the world ends.

I Used CBD-Infused Beauty Products for a Month, and It Was Actually Freaking Amazing

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Let’s just say my beauty routine was, um, elevated.

“So, it gets you high?” This is the first question everyone asks after hearing about my recent love affair with CBD oil (or cannabidoil, which is a chemical compound extracted from marijuana plants that—spoiler alert—is also completely non-psychotropic, meaning sorry, it won’t get you high). But I wasn’t seeking my typical Sunday Scary fix when I replaced half of my beauty routine with CBD infused products for a month; I was after the oil’s other rumored, yet equally excellent, topical benefits: the soothing, calming, and even wrinkle-fighting effects. Yup.

CBD oil is darling of the herbal community and, when ingested (through capsules, tinctures, or foods, like chocolate and gummies), is typically used to help with anxiety and insomnia, or even promote clear-headedness. And yes, it’s legal. Ish. Maybe. (Laws are constantly changing, and it totally depends on the form of CBD you’re getting—as in whether or not it’s totally THC-free—and what state you live in). And while the medical community has yet to really examine THC’s little sister for its medicinal purposes, the beauty world has certainly recognized its potential as an ingredient label hero.

“There’s definitely a lack of research on the subject, but the studies that are out there suggest that CBD is anti-inflammatory and potentially antimicrobial, meaning it could help fight bacteria and pathogens,” says Joyce Imahiyerobo-Ip, MD, director of cosmetic dermatology at South Shore Medical Center in MA, adding that CBD also has antioxidant properties, “which can result in anti-aging benefits.” And if something has the possibility of soothing my skin and calming my jitters at the same time, you best believe I’ll be slathering it all over my face and body, which is exactly what I did. And, surprise, it was actually kind of life-changing.

Chancellor Highlights UCSF’s Commitment to the Community in 2018 State of the University

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UCSF Chancellor Sam Hawgood, MBBS, delivers his 2018 State of the University address in Cole Hall at the Parnassus Heights campus. Photo by Susan Merrell

UC San Francisco has a “social and moral responsibility” to get involved in its communities by addressing health disparities, enabling access to science education and tackling homelessness, among other ways, Chancellor Sam Hawgood, MBBS, said in the 2018 State of the University address.

In his fifth annual address, Hawgood focused on the deep connections the University has to the Bay Area and its people. He also began by calling attention to UCSF’s role in the national community, mourning recent violent attacks in Pennsylvania and Kentucky against religious and racial minorities.

“I want to acknowledge the pain, sorrow, and outrage that many of you feel here today and when any one of these heinous events occur,” he said. “Caring and healing are two words in our mission statement. We generally mean them to represent our work with one patient and one family at a time, but caring and healing can also be caring for our own family at UCSF and the communities we serve.”

Hawgood’s address, titled “Commitment to the Community,” underscored UCSF’s longstanding commitment to social justice and highlighted innovative programs that are improving the health and well-being of the most vulnerable populations. The chancellor also pointed to a year of significant growth for UCSF – financially, physically and in its impact – and acknowledged the supportive community that helped make it possible.

State of the University 2018

Watch the full State of the University address from Oct. 30, including the chancellor’s speech from Cole Hall and a presentation from UCSF Benioff Children’s Hospital Oakland.

“Throughout its history, UCSF has enjoyed tremendous support from the communities in which we are embedded, from our elected officials, our amazing volunteers and supporters, our neighbors and the public more generally. This ongoing support is central to our growth and success in the future,” Hawgood said to the crowd in Cole Hall on the Parnassus campus. The speech was simulcast to Mission Bay, UCSF Fresno as well as UCSF Benioff Children’s Hospital Oakland.

“As we look to the future, it is clear that UCSF – as one of the Bay Area’s founding institutions – is positioned well to put our considerable resources, both human and fiscal, to work on making life better for families, neighbors, patients and future generations.”

Growth and Achievement

Hawgood began by recapping the many institutional achievements and milestones that reflected UCSF’s growing impact over the past year: Among them, UCSF Medical Center again ranked the best hospital in California, and UCSF received more National Institutes of Health research funding than any other public institution.

This has resulted in a strong financial position for UCSF: Last fiscal year, total revenues supporting core activities increased nearly 70 percent to just over $7 billion, compared to $4 billion five years ago, he reported.

Theresa O’Brien (from left), PhD, associate chancellor; Daniel Lowenstein, MD, Executive Vice Chancellor and Provost; and Talmadge E. King Jr., MD, Dean of the School of Medicine, react after watching a video at the State of the University address. Photo by Susan Merrell

More than half of that comes from patient revenue, with growing demand for UCSF Health services. In the same period, UCSF provided $384 million in undercompensated care, including care for uninsured patients and underreimbursed care to Medi-Cal patients. Research contracts and grants also have increased and accounted for about 30 percent of UCSF’s revenue.

“By many measures – our ranking among the nation’s top hospitals, the grants awarded for our scientific research, the quality of our learners, and our firm financial footing, put UCSF as one of the premier health science universities in the world,” he said.

in the world,” he said.

Meanwhile, the schools have reimagined and expanded programs to better support trainees and students:

Hawgood also reported progress with creating a more diverse and inclusive environment. For instance, through the work of the School of Medicine’s Differences Matter initiative, 40 percent of its incoming class self-identified as underrepresented in medicine, the highest percentage in UCSF history.

As UCSF works on the next strategic plan in diversity, equity and inclusion, the chancellor acknowledged there’s still “much more work to do.” The last staff engagement survey identified that black and Hispanic employees feel less engaged and less supported in their work than their white and Asian co-workers, and UCSF is working on an action plan to address this, he said.

Fundraising Campaign Reaches Milestone

One year since publicly launching an ambitious, $5 billion fundraising campaign, Hawgood reported extraordinary success.

Since the beginning of the quiet phase of the campaign in 2014, UCSF: The Campaign has raised nearly $4.2 billion. Of that, $1.2 billion was raised in gifts, grants and pledges just last year: “We are one of only a very small handful of universities that have ever reached the billion-dollar threshold in a single year,” he said.

The support also has been broad, with nearly 113,000 donors, 70,000 of whom are new to UCSF.

“While this success underscores the scale of bold ideas that are inspiring our donors, it also tells a story about our community,” he said. “More and more faculty members have been approaching me – not as individuals with their own needs, but rather as teams with a well-thought-out collaborative vision about how they plan to work together to tackle even larger, even more complex problems.”

The funding for the campaign will go to support myriad programs and projects across UCSF, including more than $1 billion for faculty and students, which is more funding than any other area of the campaign. One gift that Hawgood said he is particularly proud of is a donation, made by an alumna of the University’s PhD program, to support the recruitment and retention of women in science.

Chancellor Sam Hawgood speaks about the $500 million commitment from the Helen Diller Foundation that will support a new hospital at Parnassus Heights. Photo by Susan Merrell

In addition, Hawgood spotlighted three major recent gifts, including the funding of the UCSF Bakar ImmunoX Initiative, which will drive a team approach to analyzing the role of the immune system across diseases; a $20 million gift to establish the new UCSF Dolby Family Center for Mood Disordersthat will allow ambitious precision-medicine treatments and diagnostic tools for severe mood disorders; and the $500 million commitment from the Helen Diller Foundation that will support a new, world-class hospital at Parnassus Heights.

The new hospital is one part of an inclusive planning process for Parnassus Heights, and the chancellor said UCSF expects to share “a roadmap to sustain our mission of conducting top-tier research, clinical care, and education here on Parnassus Heights next year.”

Serving Our Community

UCSF’s work in the community dates back more than 100 years, Hawgood said, pointing to the work of the physicians and trainees who rushed to treat victims of the 1906 earthquake. That commitment has carried through the century with UCSF programs that include health and educational outreach.

Hawgood called out three longstanding community programs: the UCSF School of Dentistry’s Community Dental Clinic, a student-run operation that has provided free dental services to the city’s homeless and low-income residents for 25 years; the UCSF Alliance Health Project, formed in the early years of the AIDS epidemic and now provides mental health and substance abuse services to more than 3,500 people each year; and the Center for Science Education and Outreach, which has supported science education for tens of thousands of public school students over 20 years.

To spotlight some of the forward-thinking work to address social injustices in the community, Hawgood invited two guest speakers, Dayna Long, MD, medical director for the Department of Community Health and Engagement at UCSF Benioff Children’s Hospital Oakland, and Margot Kushel, MD, the new director of the UCSF Center for Vulnerable Populations.

Speaking from UCSF Benioff Children’s Hospital Oakland, Long described the huge disparities in health outcomes for children of color, children of immigrants and those who experience poverty, disability, discrimination and significant trauma.

“These disparities are not simply a function of access to health care. It is not genes or germs that primarily determine our well-being,” she said. “The biggest factors are our social and economic circumstances – conditions that have not traditionally been addressed by the health care system. At UCSF, we’re challenging this traditional paradigm and are changing our approach to the practice of medicine.”

Dayna Long, MD, speaks from the UCSF Benioff Children’s Hospital Oakland as a part of the 2018 State of the University address. Long spoke about her work to address toxic stress in children. Photo by Noah Berger

Long’s work studying the effects of what’s known as toxic stress led her and colleagues to establish the UCSF Child Health Equity Institute, which brings together experts in health equity science, clinical innovation, community engagement and education.

Toxic stress, which is caused by exposure to serious or prolonged trauma like sexual assault, separation from caregivers, witnessing violence or being homeless, can affect a child’s DNA, brain development, immune system, and contribute to health problems such as depression and diabetes. “These challenges are examples of health inequities – the systemic, ingrained and unjust barriers that keep entire segments of children from being well,” she said.

The experts at the UCSF Child Health Equity Institute are helping advance science-based solutions for health inequity by testing screening tools, identifying biologic markers of stress, developing new mental health interventions, and training future leaders from diversity backgrounds. “Today, we challenge ourselves to be better, we challenge ourselves to treat every child like our own,” she said.

Joining Hawgood in Cole Hall, Kushel shared UCSF’s efforts to reduce homelessness and its effects on health.

Kushel described seeing firsthand the devastating effects of homelessness on patients she treated at Zuckerberg San Francisco General Hospital. The work over the past 20 years for Kushel stems from her experience treating patients at ZSFG and then noticing that days later the same patients would return even sicker than before. “I knew that we could do better,” she said.

Research has shown that homelessness is among the most powerful predictors of health outcomes, she said, and that “for people who are homeless, there is no medicine as powerful as housing.”

Margot Kushel, MD, speaks at Cole Hall during the State of the University address. Kushel talked about her work to reduce homelessness. Photo by Susan Merrell

Kushel highlighted the work of the Emergency Department Social Medicine consult service at ZSFG. Together, teams of social workers, care coordination nurses, pharmacists, patient care coordinators and improvement specialists help connect patients with services in the community. This year alone, the service has helped 1,000 patients with complex medical and social needs, prevented more than 230 hospitalizations, and enabled many patients to exit homelessness.

“Those of us who are health care providers, scientists, students and scholars have a responsibility to amplify the voices of the patients we serve – to involve ourselves in public discourse and to seek more just policies,” Kushel said.

“At a time when the principles of scientific practice and the foundations of scientific knowledge are under assault, it is more important than ever that all of us stand up for the crucial role of science in society,” she added. “But, we also need to step back – to allow and encourage others to speak. And we need to listen to what they are telling us.”

‘Continue to Stand Up and Speak Up’

Hawgood called on everyone at UCSF to use our collective power to continue advancing social justice.

“Unquestionably, we are living in extraordinarily challenging times,” Hawgood said in his closing. “While we as a society face complex problems at the local, national and global levels, I remain very optimistic about the contributions that UCSF, we as a community, can make to solving these problems.”

One easy action is to volunteer, Hawgood said. To make it easier to connect with opportunities in the community, UCSF has a program called UCSF Volunteers that outlines how managers and staff can work together for a common cause, strengthening their connection to one another and UCSF’s mission.

A second action is voting on Nov. 6.

“Many issues are at stake in these midterms: from protecting health care for those with pre-existing conditions to defending transgender identity,” he said. “The power of our UCSF community is more than 30,000 strong, and we can make a difference.”

New Method Of Breast Reconstruction May Reduce Pain For Some Cancer Survivors

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Hani Sbitany, MD, a plastic and reconstructive surgeon at UCSF Health, performs a breast reconstruction surgery. Sbitany is one of a few surgeons using a procedure that is less invasive and has a less painful recovery. Photo by Susan Merrell

For nearly four decades, the main option for breast reconstruction for women who had to undergo a mastectomy was to place implants under the main chest muscle – a procedure that often results in chronic pain and muscle weakness in the chest and arms.

It also creates a strange unsightly contraction of the breasts and chest whenever the main muscle – the pectoralis major – contracts, called animation.

“Whether it’s loss of strength, whether its chronic pain or whether animation deformity – there are drawbacks to putting these implants under the muscle,” said Hani Sbitany, MD, a plastic and reconstructive surgeon at UCSF Health.

Now, Sbitany is one of a handful of surgeons who are pioneering and studying the outcomes of a new approach that is less invasive, has a less painful recovery and results in more natural looking breasts.

Hani Sbitany, MD

Significant Improvement for Patients

The procedure is called a prepectoral reconstruction, and involves placing the implants on top of the pectoralis muscle, just under the skin where breast tissue naturally resides.

For women, the difference is significant. Just ask Deborah Cohan, MD, MPH.

Cohan was diagnosed with breast cancer in 2013. Within a few months she had a complete mastectomy, followed by chemotherapy and later breast reconstruction. At the time the prevailing method was still to place the implants under the pectoral muscles.

“After the reconstruction I was having tingling symptoms in my hands and arms … when I would raise my arms, my hands would go white,” said Cohan, a physician at UC San Francisco. She also developed left shoulder pain and felt substantial pain in her chest.

Whether it’s loss of strength, whether its chronic pain or whether animation deformity – there are drawbacks to putting these implants under the muscle.

Hani Sbitany, MD

Plastic and Reconstructive Surgeon at UCSF Health

“It was hard to work at the computer, I couldn’t open doors or jars without feeling chest wall pain,” said Cohan. Cohan says she tried all kinds of things to address the pain: physical therapy, chiropractic adjustments, acupuncture, conscious dance and meditation – but she chose not to use opiate medicines for the pain. “I learned to live with chronic pain but not cover it up.”

The surgery also left Cohan with animation: “Whenever I would flex my pectoralis muscle, the implants would move up my chest, so I had to wear shirts with a super high collar or my breasts would fall out, basically.”

Deanna King had a similar experience. After being diagnosed with aggressive breast cancer in 2013, within a few weeks she had a complete mastectomy and reconstruction.

“When you have your implant under the pectoral muscle, oftentimes you get this weird, jerky animation, so when you move your breasts sort of jump up and down,” said King.

Pain and weakness often stem from the invasiveness of the surgery, during which the surgeon dissects the pectoralis muscle, cut parts of it, separates it from the ribs and create a pocket underneath it in which the implant sits – permanently stretching it for life, said Sbitany, who is an associate professor of Surgery at UCSF.

In hindsight, it may seem obvious that breast implants should be placed above the pectoral muscle.

But the reason surgeons began putting implants underneath the chest muscle in the 1970s is that placing implants directly under the skin resulted in higher infection rates. Additionally, the immune system often reacted to the foreign body leading to significant buildup of scar tissue that encapsulated the implant. Other times the skin wore away and the implant was exposed.

Putting the implants under the large pectoralis muscle mostly solved these problems because muscles receive high blood flow, which helped reduce the buildup of scar tissue around the implants and reduce infections.

New Technology for Implants

But in recent years, Sbitany and other surgeons have found a way to keep the implant on top of the muscle and address those problems: they’re surrounding the implants with a biologic mesh, essentially a thin layer of collagen.

“Now we can put the implants under the skin and a subsequent next layer of biologic mesh to protect the implant – so the implants are not right under skin, so the implants are sitting under a layer of mesh, in a pocket we’ve created using the mesh,” said Sbitany. “In essence, we have the ability to do a totally muscle-sparing, muscle-preserving breast reconstruction.”

A whole host of elements that have evolved in recent decades have made the above-the-muscle approach not only feasible, but a far better option, said Maurice Nahabedian, MD, formerly of Johns Hopkins University and Georgetown University and now in private practice.

Nahabedian says the early generation of breast implants were “pretty questionable”; they tended to rupture and produce a lot of inflammation and scar tissue, and reconstructive failure was really high.

“But what’s changed is now we have acellular dermal matrices (biologic mesh), we do fat grafting all the time, we have better quality mastectomies and we have better implants. And we’ve really been able to capture the benefits. I can’t even imagine going back to putting an implant back under the muscle anymore.”

Ratcheting Up the Body’s Defenses Against Ebola

The group’s first study, conducted in collaboration with Christopher Basler, PhD, at Georgia State University, identified 194 virus-human interactions involving six Ebola proteins. The scientists narrowed their focus to one specific point of contact between an Ebola protein called VP30 and a human protein called RBBP6.

The interaction first caught their attention because it was such a strong one, but RBBP6 ended up being a particularly intriguing protein because it has emerged in other virus-protein interaction maps, leading Krogan to believe it plays an important role in the immune system.

Ebola virus.

It turns out that RBBP6 mimics another Ebola protein called NP. VP30 and NP need to bind to one another in order for the Ebola virus to replicate. However, the human protein RBBP6 interrupts this process by attaching to VP30 instead. So, by blocking the connection between the two Ebola proteins, RBBP6 effectively stops the virus from replicating.

To their surprise, the researchers didn’t discover a way the virus attacks the host (in this case, human cells). Rather, they found a way for the host to fend off the virus.

“We often find viral proteins that have evolved to mimic human proteins, but here it’s the opposite,” said Jyoti Batra, PhD, one of the first authors of the paper and a postdoctoral scholar at Gladstone who was formerly in Basler’s laboratory at Georgia State University. “It appears our body has a natural way to fight off Ebola infection, and the virus hasn’t gotten around it. Keep in mind, we still don’t have great mechanisms to fight off Ebola, but without this protection the virus would be even deadlier.”

To test this theory, Batra worked with the study’s other first author Judd Hultquist, PhD, who conducted the research as a postdoctoral scholar in Krogan’s lab at Gladstone and UCSF and is now an assistant professor at Northwestern University Feinberg School of Medicine. Together, they engineered human cells to either have none of the protein RBBP6 or much higher levels than normal. Then, they infected the cells with the Ebola virus. In cells with no protective protein, infection rates went up fivefold. But the cells with extra protein strongly prevented infection by the virus.

Krogan’s team is now working to identify drugs that can mimic the effects of RBBP6 to fight off Ebola infection.

“This is a key interaction,” said Krogan. “The question is whether we can manipulate it in an effective pharmacological way for it to have therapeutic value.”

The fat grafting helps to be able to add protection around the implant and better contour the shape of the new breast, he said.

For patients like Cohan and King, that has meant a host of improvements.

Four years after her original implants, in a fluke cab ride conversation with a stranger, Cohan learned that prepectoral breast reconstruction was now an option. Cohan did some research in the Bay Area and found UCSF’s Sbitany. She opted to undergo another surgery to remove the subpectoral implants and put new implants with biological mesh just under the skin.

Deborah Cohan, MD, MPH, had the prepectoral breast reconstruction surgery, which reduced her ongoing pain. Photo courtesy of Deborah Cohen

“So after the surgery, not only did my animation deformity go away and my chest pain get better, the pain in my left shoulder completely disappeared,” Cohan said. The shoulder pain stemmed from the previous detachment of the pectoralis muscle from the ribs, which then pulled at the shoulder and arm muscles.

“And, I was finally able to take a deep breath,” she said. “In fact, my first conscious moment in the recovery room after surgery was taking the deepest inhalation I was able to take in five years.”

King’s decision to undergo another reconstruction surgery was more complicated. She had been diagnosed with terminal cancer, so she initially thought she wouldn’t bother with a corrective surgery. But then she decided she might as well live in comfort.

Both women are active people, and grateful to freedom of movement back.

“I’m so appreciative that Hani listened to me, and to other women,” King said. “It’s very easy for surgeries that seem just fine, for surgeons to continue doing it, and there isn’t necessarily a pressure to innovate unless doctors listen to patients.”

Further Research About the Benefits

Surgeons like Sbitany and Nahabedian have been promoting the prepectoral technique at national surgery conferences and also publishing scientific research.

Not only is this surgery less invasive, Sbitany is also researching outcomes for women who have prepectoral breast reconstruction followed by radiation therapy.

“There’s a much higher complication rate when you think about breast reconstruction of any type with radiation. It’s a real deterrent for breast reconstruction. But we’ve found this is a very safe option in the setting of radiation,” said Sbitany.

Another benefit of avoiding dissecting the pectoral muscle is a substantial reduction in pain.

“Our preliminary data shows that by avoiding the muscle and offering a prepectoral approach we’re potentially reducing opioid medication and narcotic medication use by up to 70 percent in our patients, just by avoiding the muscle dissection,” said Sbitany.

“In this day of the opioid epidemic, that’s really significant.”

Drug Targets for Ebola, Dengue, and Zika Viruses Found in Lab Study

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Insight Into How Three of the World’s Most Devastating Viruses Interact With Human Cells Opens the Door for Much-Needed Treatments

No drugs are currently available to treat Ebola, Dengue, or Zika viruses, which infect millions of people every year and result in severe illness, birth defects, and even death. New research from the Gladstone Institutes and UC San Francisco may finally change that.

Scientists identified key ways the three viruses hijack the body’s cells, and they found at least one potential drug that can disrupt this process in human cells. What’s more, they discovered how the Zika virus might cause microcephaly in infants, the first step in developing a way to stop the disease.

Published in back-to-back papers in the Dec. 13, 2018, issue of the scientific journal Cell, the researchers employed a technique called protein–protein interaction mapping to probe the three viruses. The method uses human cells in laboratory dishes to create a map of each point of contact between viral and human proteins.

The scientists, whose work was conducted under the umbrella of the Host Pathogen Mapping Initiative launched by the Quantitative Biosciences Institute (QBI) at UCSF, are using these comprehensive maps to target the interactions and try to kill the infection.

“We’ve employed our systematic protein–protein interaction strategy on Ebola, Dengue, and Zika to get a better sense of how these three very problematic viruses hijack, rewire, and infect human cells,” said the leader of the two studies Nevan Krogan, PhD, a senior investigator at the Gladstone Institutes, the director of QBI at UCSF, and a professor of cellular and molecular pharmacology at UCSF. “To me, what’s most interesting is when we see the same human machinery being hijacked by seemingly very different viruses and different pathogenic proteins.”

By comparing one virus’s map to another, the researchers can find human proteins that are routinely targeted by several different viruses, and that could potentially be involved in other types of human disease as well.

Nevan Krogan, PhD, lead of the two studies.

This means targeting those human proteins – which could be considered the weak points of human biology – may be effective in treating many different diseases. For instance, Krogan and his team found that a drug candidate initially explored for cancer treatment can successfully wipe out the infection caused by Dengue and Zika in human cells.

Ratcheting Up the Body’s Defenses Against Ebola

The group’s first study, conducted in collaboration with Christopher Basler, PhD, at Georgia State University, identified 194 virus-human interactions involving six Ebola proteins. The scientists narrowed their focus to one specific point of contact between an Ebola protein called VP30 and a human protein called RBBP6.

The interaction first caught their attention because it was such a strong one, but RBBP6 ended up being a particularly intriguing protein because it has emerged in other virus-protein interaction maps, leading Krogan to believe it plays an important role in the immune system.

Ebola virus.

It turns out that RBBP6 mimics another Ebola protein called NP. VP30 and NP need to bind to one another in order for the Ebola virus to replicate. However, the human protein RBBP6 interrupts this process by attaching to VP30 instead. So, by blocking the connection between the two Ebola proteins, RBBP6 effectively stops the virus from replicating.

To their surprise, the researchers didn’t discover a way the virus attacks the host (in this case, human cells). Rather, they found a way for the host to fend off the virus.

“We often find viral proteins that have evolved to mimic human proteins, but here it’s the opposite,” said Jyoti Batra, PhD, one of the first authors of the paper and a postdoctoral scholar at Gladstone who was formerly in Basler’s laboratory at Georgia State University. “It appears our body has a natural way to fight off Ebola infection, and the virus hasn’t gotten around it. Keep in mind, we still don’t have great mechanisms to fight off Ebola, but without this protection the virus would be even deadlier.”

To test this theory, Batra worked with the study’s other first author Judd Hultquist, PhD, who conducted the research as a postdoctoral scholar in Krogan’s lab at Gladstone and UCSF and is now an assistant professor at Northwestern University Feinberg School of Medicine. Together, they engineered human cells to either have none of the protein RBBP6 or much higher levels than normal. Then, they infected the cells with the Ebola virus. In cells with no protective protein, infection rates went up fivefold. But the cells with extra protein strongly prevented infection by the virus.

Krogan’s team is now working to identify drugs that can mimic the effects of RBBP6 to fight off Ebola infection.

“This is a key interaction,” said Krogan. “The question is whether we can manipulate it in an effective pharmacological way for it to have therapeutic value.”

Defeating Dengue and Zika

In the second paper, Krogan’s laboratory worked with researchers at Icahn School of Medicine at Mount Sinai and Baylor College of Medicine. They explored the related Dengue and Zika viruses, which are both transmitted by mosquitos and cause similar clinical symptoms.

The scientists hypothesized that if the two viruses interact with human proteins in similar ways, targeting those protein interactions could be the best way to fight the infections. They also mapped the interactions between the Dengue virus and mosquito proteins to compare it to the human–virus protein maps.

Infection of developing human brain with the Zika virus (green) highlights susceptibility of radial glial cells during fetal development. Image by Elizabeth Di Lullo

“There is something really fascinating about a virus that can do the same thing in two organisms, the human and the mosquito, that have diverged over hundreds of millions of years of evolution,” said Priya Shah, PhD, an assistant professor of chemical engineering and microbiology and molecular genetics at UC Davis who conducted the research while she was a postdoctoral researcher at UCSF. “The virus replicates essentially in the same way in both human and mosquito cells. So, if we can home in on the shared parts of these cells that are exploited by the virus, we could identify a potentially powerful therapeutic target.”

Comparing the three maps, the scientists identified one interaction that occurred in both viruses and both host species: the viral protein NS4A and the host protein SEC61. SEC61 is known to play a critical role in some forms of cancer, and Krogan’s colleague at UCSF, Jack Taunton, PhD, had previously developed compounds targeting these proteins as potential anti-cancer drugs. When the compounds were added to the human and mosquito cells, they effectively wiped out both the Dengue and Zika infections.

“We’ve developed an early-stage compound that has very potent antiviral activity against both Zika and Dengue in human and mosquito cells,” said Taunton, a professor in the Department of Cellular and Molecular Pharmacology at UCSF. “Now we need to tweak the molecule to optimize its safety and efficacy before it can be tested in patients.”

“Here’s a great example of repurposing a compound originally developed for one disease and using it to have an effect on another disease,” said Krogan. “It comes back to the bigger picture: by looking across these datasets and across diseases, we can find new connections and innovative solutions.”

Understanding How Zika Causes Microcephaly

Although Dengue and Zika are very similar, only Zika causes the devastating birth defect microcephaly. So, in the final set of experiments, Krogan’s team looked for examples where Zika proteins interacted with human proteins, while Dengue proteins did not.

One interaction that especially stood out was between the Zika protein NS4A and the human protein ANKLE2, which is important for brain development. Mutations in ANKLE2 have previously been linked to hereditary microcephaly.

The scientists found that the Zika protein appears to inhibit the function of ANKLE2, ultimately impairing brain development and leading to microcephaly. The researchers plan to use this knowledge to start developing ways to target ANKLE2 to prevent Zika-related microcephaly.

Looking for Overlaps

The two studies have given the scientists promising leads either to develop new therapies for Ebola, Dengue, and Zika, or repurpose existing ones. By targeting the protein interactions identified in the two studies—especially the human proteins RBBP6 and SEC61—the researchers were able to eradicate all three viruses from human cells, a crucial start in developing potential treatments for the diseases.

The research will continue under the BioFulcrum Viral and Infectious Disease Research Program at Gladstone and Host Pathogen Mapping Initiative at UCSF, which was recently bolstered by a center grant from the National Institutes of Health for $8 million to focus on tuberculosis and Staphylococcus. The two broad-reaching research programs have previously produced protein–protein interaction maps for HIV, tuberculosis, hepatitis C virus, herpesvirus, human papillomavirus, and chlamydia.

“We’re starting to see there’s overlap among the proteins hijacked by different viruses,” said Krogan. “Not only that, but these same proteins are often mutated in diseases with genetic roots, like cancer and autism. The more commonalities we can find between seemingly unrelated diseases, the better we can identify therapies to treat these devastating conditions.”

Authors: Additional contributors to the Ebola study include John Von Dollen, Laura Satkamp, Gwendolyn M. Jang, Robyn Kaake, Paige Haas, Carson B. Schmidt from Gladstone, UCSF and QBI; Dandan Liu, Gabriel I. Small, Daisy W. Leung and Gaya K. Amarasinghe from the Washington University School of Medicine; Olena Shtanko, Eusondia Arnett, Manu Anantpadma, Ann Reyes, Larry S. Schlesinger, and Robert A. Davey from the Texas Biomedical Research Institute; Priya Luthra from Georgia State University; Toni M. Schwarz from the Icahn School of Medicine at Mount Sinai; and Douglas J. LaCount from Purdue University.

Additional contributors to the Zika and Dengue study include Danielle L. SwaneyJeffrey R. Johnson, John Von Dollen, Laura Satkamp, Billy Newton, Ruth Hüttenhain, Michael Shales, Erica Stevenson, Leila Shokat, and Katherine S. Pollard from Gladstone, UCSF and QBI; Phillip P. Sharp, Tierney Baum, Amanda Everitt, Orly LaufmanMichel TassettoA. Jeremy Willsey, and Raul Andino from UCSF; Nichole Link and Hugo J. Bellen at Baylor College of Medicine; TongTong Zhu, Sebastian Aguirre, Shashank Tripathi. Laurenec G. Webb, Adolfo Garcia-Sastre, Ivan Marazzi, and Ana Fernandez-Sesma from Icahn School of Medicine at Mount Sinai; Holly R. Ramage and Sara Cherry from the University of Pennsylvania; Marine J. Petit from UC Davis; Gabriel N. Iglesias and Andrea V. Gamarnik from the Fundación Instituto Leloir-CONICET; and Vinod Balasubramaniam from Monash University Malaysia.

Funding: The Ebola work was supported by NIH grants P50GM082250, U19AI106754, R01AI120694, P01AI063302, U19AI109664, U19AI109945, P01120943 and R01AI114814; amfAR grant 109504-61-RKRL with funds raised by generationCURE; a Forum grant from the Texas Biomedical Research Institute; BioSURf and HHMI; and the Georgia Research Alliance Eminent Scholar Program in Microbial Pathogenesis.

The Zika and Dengue work was supported by NIH/NIAID F32AI112262; NIH/NINDS F32NS092270; DOD/DARPA HR0011-11-C-0094; NIH/NIAID U19AI1186101; NIH/NIGMS P50 GM082250; NIH/NIAID R01AI07345 and R21AI116022; UCSF Breast Cancer Research Funds; NIH/NINDS U54NS093793; NIH/OD R24OD022005; and the Huffington Foundation supported by HHMI.

Disclosures: Jack Taunton is a cofounder and shareholder of Global Blood Therapeutics, Principia Biopharma, Kezar Life Sciences and Cedilla Therapeutics. Taunton and Phillip P. Sharp are listed as inventors on a provisional patent application describing PS3061.

UC San Francisco (UCSF) is a leading university dedicated to promoting health worldwide through advanced biomedical research, graduate-level education in the life sciences and health professions, and excellence in patient care. It includes top-ranked graduate schools of dentistry, medicine, nursing and pharmacy; a graduate division with nationally renowned programs in basic, biomedical, translational and population sciences; and a preeminent biomedical research enterprise. It also includes UCSF Health, which comprises three top-ranked hospitals – UCSF Medical Center and UCSF Benioff Children’s Hospitals in San Francisco and Oakland – as well as Langley Porter Psychiatric Hospital and Clinics, UCSF Benioff Children’s Physicians and the UCSF Faculty Practice. UCSF Health has affiliations with hospitals and health organizations throughout the Bay Area. UCSF faculty also provide all physician care at the public Zuckerberg San Francisco General Hospital and Trauma Center, and the SF VA Medical Center. The UCSF Fresno Medical Education Program is a major branch of the University of California, San Francisco’s School of Medicine.

Sex Chromosomes Hold the Secret to Female Longevity

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Female Biology – Two X’s and Ovaries – Extends Life and Protects Mice From Aging

Around the world, women outlive men. This is true in sickness and in health, in war and in peace, even during severe epidemics and famine. In most animal species, females live longer than males.

Now, scientists at UC San Francisco have zeroed in on a possible genetic mechanism for this highly durable phenomenon, that – while it does not preclude the influence of other biological, social and environmental factors – suggests an important role for the second X chromosome, which is present in female mammals. The X chromosome contains many genes related to the brain, and it is crucial for survival. Without at least one X, an animal cannot live. The Y chromosome, present only in males, contains very few genes other than those that create secondary sex characteristics, like male genitals and facial hair, and it is not necessary for survival.

The researchers gave experimental mice four different combinations of chromosomes and gonads: the two found in nature – XX with ovaries and XY with testes – and two others created in the laboratory – XX testes and XY ovaries. The mice were genetically identical except for their sex chromosomes, but even when everything else about them, including their environment, was the same, having two X’s promoted survival. When two X’s were combined with ovaries, the mice lived to the furthest edges of the mouse lifespan.

“We’ve long wondered what causes female longevity,” said Dena Dubal, MD, PhD, associate professor of neurology at UCSF and senior author of the study published in Aging Cell. Dubal is the David Coulter Endowed Chair in Aging and Neurodegenerative Disease, and a member of the Weill Institute for Neurosciencesat UCSF. “One can imagine nature has driven females to evolve this way. When you’re living longer, you can really ensure the well-being of your offspring, and maybe even their offspring.”

Dena Dubal MD, PhD, senior author of the study (center).

The experiment, conducted by Emily Davis, a student in the Biomedical Sciences Graduate Program at UCSF, is the first mechanistic study to show that females live longer than males, and that XX largely governs this trait in aging mice. It took several years to complete, since the mice were observed until they either died or survived until 30 months. Dubal and her team used the Four Core Genotypes (FCG) model developed two decades ago and then championed by UCLA scientist Arthur Arnold, PhD, for rigorous study of sex differences.

The technique manipulates the Sry gene, which normally resides on the Y chromosome and causes testes and other masculine features to develop. In the FCG mice, Sry has been moved to a different chromosome that does not determine sex, so it can be inherited whether or not a mouse has a Y chromosome.

The researchers found that having both female sex chromosomes and female gonads extended life in mice that were 12 to 30 months old, the mouse equivalent of midlife to old age. But most of the effect came from the sex chromosomes. The XX mice lived longer than the XY mice, whether either one had ovaries or testes. But the mice that lived the longest had ovaries, in addition to two X chromosomes – in other words, they displayed natural female mouse biology.

“This suggests that the hormones produced by female gonads increase lifespan in mice with two X chromosomes, either by influencing how the mouse develops or by activating certain biological pathways during their lives,” Dubal said.

When comparing the two different types of genetically female mice – those with ovaries and those with testes – the researchers found having two X’s plus ovaries enabled mice to live longer, beginning at 21 months, which is toward the end of a normal mouse lifespan. But for the laboratory mice who were genetically female but hormonally male – two X’s plus testes – the second X chromosome only protected them from dying earlier in life without extending their lives beyond the normal mouse lifespan. These benefits trailed off by the time the mice were 23 months old.

“For an expanded lifespan, the mice needed to have ovaries working with XX,” said Iryna Lobach, PhD, assistant professor of epidemiology and biostatistics at UCSF, who did the statistical analysis that found these cutoff points. “But in terms of living a normal lifespan, it didn’t matter if they had ovaries or testes. As long as they had XX, they escaped early death during aging.”

A neurologist and neuroscientist who specializes in healthy aging, Dubal is actively investigating how the X and Y chromosomes exert such far-reaching influences.

“We don’t yet understand how the second X chromosome decreases mortality in aging,” she said.

But there is much in the scientific literature to suggest the profoundly protective effect of having a second X chromosome. In females, half of the XX pair is randomly “silenced” – or turned off – in each cell of the body. So when there are defects, cells with the healthy X can compensate for those with the unhealthy X.  And even without defects, the X that is silent still expresses itself somewhat, causing more X chromosome to be expressed in each female cell compared to male cells. Dubal said another possible explanation, which remains to be tested, is that the Y could somehow be harmful.

“When things go wrong in aging, having more of the X chromosome, along with its diversity of expression, could be really beneficial,” Dubal said.

Authors: Emily Davis, Biomedical Sciences Graduate Program at UCSF; Iryna Lobach, PhD, assistant professor of epidemiology and biostatistics at UCSF; Dena Dubal MD, PhD, associate professor of neurology, David Coulter Endowed Chair in Aging and Neurodegenerative Disease, and a member of the Weill Institute for Neurosciences at UCSF.

Funding: Supported by the NSF grant 1650113, NIH grants AG034531 and NS092918, Coulter-Weeks Foundation, Bakar Foundation, American Federation for Aging Research, and Glenn Foundation.

Disclosures: None.

UC San Francisco (UCSF) is a leading university dedicated to promoting health worldwide through advanced biomedical research, graduate-level education in the life sciences and health professions, and excellence in patient care. It includes top-ranked graduate schools of dentistry, medicine, nursing and pharmacy; a graduate division with nationally renowned programs in basic, biomedical, translational and population sciences; and a preeminent biomedical research enterprise. It also includes UCSF Health, which comprises three top-ranked hospitals – UCSF Medical Center and UCSF Benioff Children’s Hospitals in San Francisco and Oakland – as well as Langley Porter Psychiatric Hospital and Clinics, UCSF Benioff Children’s Physicians and the UCSF Faculty Practice. UCSF Health has affiliations with hospitals and health organizations throughout the Bay Area. UCSF faculty also provide all physician care at the public Zuckerberg San Francisco General Hospital and Trauma Center, and the SF VA Medical Center. The UCSF Fresno Medical Education Program is a major branch of the University of California, San Francisco’s School of Medicine.