Medications known as PARP inhibitors have emerged as a promising therapy for several forms of cancer fueled by a defect in the cells’ DNA repair machinery. Yet many people with cancers caused by the defect, known as HR deficiency, who stand to benefit from PARP inhibitors remain unidentified because standard genetic panels used in the clinic do not reliably detect the cancer-causing HR deficiency.Now, scientists from Harvard Medical School (HMS) have designed an algorithm that can successfully “read” the molecular signature of the cancer-driving defect and identify patients who could benefit from treatment with PARP inhibitors.If incorporated into standard gene panel tests, the researchers said, the algorithm could greatly expand the pool of patients who stand to benefit from PARP-inhibitor therapy but currently are not getting it.A report on the work was published April 15 in Nature Genetics.“Pinpointing actionable genetic biomarkers and treating patients with drugs that specifically target the relevant cancer-driving pathways is at the heart of precision medicine. We believe our algorithm can greatly enhance physicians’ ability to deliver such individualized therapy,” said study senior author Peter Park, professor of biomedical informatics in the Blavatnik Institute at HMS.PARP inhibitors are most commonly used in breast cancer patients who have mutations in their BRCA genes. BRCA mutations can interfere with the cells’ HR machinery, a mechanism used by cells to mend harmful DNA breaks. Yet, not everyone with an HR deficiency has a BRCA mutation. In fact, many people with breast cancer who harbor HR defects do not have BRCA mutations. As a result, most commonly used genetic tests — designed to look for BRCA mutation — miss the underlying HR deficiency that can give rise to breast, ovarian, pancreatic, and other cancers. Thus, a number of cancer cases fueled by HR gene defects remain undetected by standard gene assays, the researchers said.“We suspect there are many more patients without BRCA mutations who could benefit from PARP inhibitors, but doctors do not know which ones they are. Our approach could help close that gap,” Park said.Computer to clinicGiven that HR gene defects underlie multiple cancers, researchers say they hope the new algorithm could be swiftly incorporated into genetic tests already used in hospitals.“Tens of thousands of patients with cancer are profiled with gene panels across many hospitals and we believe our algorithm can detect the molecular footprints of the underlying cancer-causing defects with much greater sensitivity,” said the study’s first author Doga Gulhan, a post-doctoral researcher in the department of biomedical informatics at HMS. “The overarching goal of such testing is to help clinicians determine the optimal treatment for each patient based on the absence or presence of a given gene defect.”The team’s analysis suggests that in the case of breast cancer alone, incorporating the algorithm into current genetic panels would double the number of patients who could benefit from PARP inhibitors. Of the 270,000 new breast cancer cases diagnosed in 2018, between 5 and 10 percent (13,500 to 27,000) are attributed to BRCA defects. Using computer simulation analysis, the researchers identified twice as many cases of breast cancer (54,000 to 27,000) bearing the genomic footprint of HR defects without BRCA mutations.Patients with breast cancer who have BRCA gene defects — reliable but not exclusive markers of HR deficiency — are already treated successfully with PARP inhibitors. But the researchers point to emerging evidence suggesting many other cancers driven by HR defects could also benefit from treatment with PARP inhibitors. Because the new algorithm detects the molecular signature of the HR defect, the presence of the signature could be used as a predictive biomarker for response to PARP inhibitors in a range of cancers, Park said.The language of cancerEach tumor has a language of its own and leaves a written molecular trail of its origins.Cancer mutations can arise from inherited malformations in gene structure or from environmental causes such as UV radiation or cigarette smoke. Each of these disruptors causes idiosyncratic alterations in the cells’ DNA. As a result, the letters of the DNA strand get scrambled — a genetic spelling error that can give rise to cancer. The new algorithm is capable of identifying characteristic patterns of such spelling errors to detect the presence of the HR defect.Detecting HR’s telltale molecular clues in genetic samples is currently possible only if a person has their entire genome — some 20,000 genes — sequenced. Such extensive sequencing, however, is not done in the clinic and is limited to research uses. By comparison, most standard genetic panels performed in the clinic analyze between 200 and 400 genes.The advantage of the new algorithm is that it can see the molecular footprints of the HR defect even in the standard clinical tests that analyze only a subset of genes. The researchers say their algorithm is better at detecting the presence of HR defects because it was “trained” on thousands of fully sequenced tumor genomes. This extensive training gives the algorithm a more expansive vocabulary that allows it to read and interpret many more molecular languages and misspellings based on far fewer molecular clues.The algorithm’s ability to spot the markers of HR deficiency from only a handful of genes and a few mutations is akin to being able to understand the meaning of a text based on a single chapter (400 or so genes) instead of the entire book (20,000 fully sequenced genes), the researchers explained.Better at reading comprehensionTo test the accuracy of their model, dubbed SigMA (Signature Mutational Analysis), the investigators measured its performance against 730 samples analyzed by whole-genome sequencing, the gold standard for mutation detection. Despite the fact that it was reading far fewer genes and fewer mutations, the SigMA model correctly identified 163 of 221 samples with HR deficiency, a 74 percent accuracy rate. This is a notable improvement over current algorithms that detect HR-deficient cancer cells at a rate of 30 to 40 percent, the team said.To gauge SigMA’s performance on a real gene panel, the researchers applied it to 878 breast tumor samples from patients who had been previously analyzed by a standard genetic test. The algorithm identified 23 percent of the tumor samples as bearing the mark of HR deficiency. The algorithm also detected previously unidentified HR defects in other types of cancers, ranging from 5 percent in esophageal cancers and 38 percent of samples in ovarian cancers.To determine whether the algorithm could accurately predict response to PARP inhibitors, the scientists analyzed results from experiments on 383 patient tumor cell lines from 14 cancer types treated with four PARP inhibitors. Breast cancer cell lines identified by the SigMA algorithm as bearing the molecular mark of HR deficiency responded better to the PARP inhibitor olaparib than cells that did not bear the molecular signature of HR deficiency. A similar effect was observed in breast cancer cell lines treated with three other PARP inhibitors. Other tumor types also responded better to PARP inhibitors if they were identified as HR-deficient by the SigMA model. The observation suggests that the algorithm can reliably identify patients who could benefit from PARP inhibitors, the team said. Related Vitamin D may slow progression of metastatic colorectal cancer Encouraging results prompt planned evaluation in large phase 3 trial Wyss Institute researchers are inventing new ways to fight the deadly disease “We have spoken with many clinicians in the past months and we have started multiple collaborations in which additional patients in clinical trials will be given the drug based on our predictions,” Park said. “We think we could make a real impact in cancer care with this computational method.”The researchers caution that the SigMA model cannot detect HR deficiencies in certain cancers with very few mutations — such as medulloblastoma, a type of brain cancer, and Ewing sarcoma, a type of bone cancer.However, as the number of publicly available fully sequenced genomes grows, the algorithm could be trained on more tumor types to detect a greater variety of genetic mutations.“The accuracy of the algorithm will vary by cancer type,” Park said. “But even when the detection rate is not as high, there still will be additional cases identified that would be otherwise missed. What this ultimately means is better targeted treatments for more people.”Study co-investigators included Jake June-Koo Lee, Giorgio Melloni, and Isidro Cortes Ciriano.The work was supported by funding from the Ludwig Center at Harvard and by the European Union through Curie grant 703543. Harnessing nature to beat cancer
GAZETTE: We’re of course currently in the midst of a follow-up survey, four years later. All degree-seeking students have until April 30 to complete it. Why is it so important to survey the community again, and what are your expectations for how this year’s survey can continue to provide positive change with regard to sexual misconduct and assault on campus?McGINN: Student voices and student input are critical to getting our approaches to sexual and gender-based harassment right, and surveys provide the best way of broadly collecting students’ experiences and perceptions and preferences. It’s essential that every few years we check in with, in essence, a new population of students on campus and learn from them.Also we are in a very different time at a societal level than we were in four years ago. #MeToo has revealed the extent to which sexual harassment and sexual violence are still painfully prevalent in our society, and it’s being talked about more and understood differently. The 2019 survey presents an opportunity for students to provide a voice against the backdrop of this movement, and we expect their responses will reflect that in a way that couldn’t have been true four years ago.NEWELL: The 2019 survey also presents us with an opportunity to begin to evaluate some of the interventions we’ve introduced in the past four years, and see if they’re beginning to actually make an impact. It’s unrealistic to believe we’ll see dramatic change even in a four-year cycle, but over time, by taking a closer look at the data, I’m hopeful we’ll begin to understand where we’re making progress, and continue to develop ways of assuring that Harvard is a safe place for everyone to work, study, and thrive.GAZETTE: What would you say to those who may be experiencing survey fatigue?McGINN: I absolutely empathize with the idea of survey fatigue, but I see this as a real opportunity to be heard. This is a case in which the University is asking every student to tell us their opinion. We are listening. There is space in this year’s survey for open response, so that students can tell us anything they want us to know. Anything at all.NEWELL: Our response rate in the previous survey was significant in the data provided, of course, but also in that it sent a message that our student body was serious about this issue. I believe there is a real danger that if our response rate is low this time around, the voice of our students will also be diminished. The women’s revolt: Why now, and where to A new student liaison committee was formed, engaging perspectives of students from across Harvard’s Schools. It is led by an Education Program Manager. Related The Title IX Office and Office of Dispute Resolution became two distinct entities. This separation allowed ODR to handle cases that fell outside the scope of the university harassment policy. It also allowed the Title IX office to expand its educational programming, and work with local coordinators to respond to disclosures of harassment. The road ahead for Title IX efforts Though Harvard has been working to reduce sexual and gender harassment for years, it’s adding to its efforts In-person bystander intervention training is now offered to students, staff, and faculty. There are more than 50 Title IX coordinators University-wide, up from 35 in 2014. The #MeToo surge against sexual abuse provides opportunities for pivotal societal change, but challenges too A new Title IX website was developed, plus new and enhanced resource materials, including an employee resource folder which outlines steps to support individuals who disclose an incident of sexual or gender-based harassment. What’s changed at Harvard since the last AAU survey in 2015? More than 25,000 members of the community have completed the University’s online Title IX training module. Last fall, all faculty and staff were required to complete a common baseline of training. On April 2, the University launched the Harvard Student Survey on Sexual Assault & Misconduct, a tool that will be used to continue to guide policies that encourage a healthy, safe, and nondiscriminatory environment across campus. (It remains open through April 30).Throughout the spring, similar surveys are being administered at 32 additional institutions of higher education as part of a cohort convened by the Association of American Universities (AAU). This is the second time Harvard has participated in such a survey from the AAU; in 2015 the University played a leading role in articulating the need for, and helping to design, the study. Its results, driven by a large response rate, helped guide significant changes to the University’s Title IX Office, its policy and procedures, and the resources offered across Harvard.The Gazette sat down with Deputy Provost Peggy Newell and Senior Associate Dean for Faculty Strategy and Recruiting at Harvard Business School Kathleen McGinn, who chairs the steering committee focused on the survey’s successful implementation, to discuss the very real impact the 2015 survey has made on Harvard on the whole and why they hope this year’s version will provide a similar positive influence for change.Q&APeggy Newell and Kathleen McGinnGAZETTE: This is now the second edition of a sexual assault and misconduct survey conducted at Harvard in collaboration with the American Association of Universities. The first, conducted in 2015, has already led to a significant increase in Title IX resources on campus. Give us a sense of the extent of the first survey’s impact.NEWELL: In 2015, the community was very active in its response to the survey. Fifty-three percent of all of Harvard’s degree-seeking students responded — the most of any of the universities that participated as part of the AAU cohort — and this meaningful, engaged input was instrumental in helping the Title IX Office and the Office for Dispute Resolution to increase the size of their teams and create a wealth of new resources.Some of those successes include an increase to more than 50 Title IX coordinators University-wide, up from 35 in 2014, and the establishment of a new student liaison committee that provides an opportunity for individuals across the University with a cross-section of perspectives to convene regularly and take stock of what Harvard is doing right, and where it needs to do more.The Title IX Office also has been instrumental in implementing required training for all faculty, staff, and students online. At the time of the 2015 survey, we had not yet done an online training for students. Since then, we’ve offered 11, and in the past two years alone, more than 25,000 members of Harvard’s community have participated in such trainings, and many more have also trained in person. The office also introduced a novel bystander intervention training in 2018, and early responses to this resource have been positive.Broadly, I truly believe it is critically important to have data to illustrate the scope of a problem in order to best target interventions with which to address it. The data collected from the 2015 survey has already made a significant impact here at Harvard. Now we need to learn more.McGINN: Organizations need to be able to make decisions based on facts. Prior to 2015, we had very little information about the prevalence and nature of sexual and gender-based harassment and sexual misconduct on campus; we had very little information on how students responded to harassment and misconduct, unless they reported it; and we believed that the ratio of reporting to incidents was very low. We also had very little insight into what we weren’t doing. Where were the real holes in the resources available in the Harvard community?Thanks to the first survey, we quickly realized that our resources for Title IX, dispute resolution, and mental health were insufficient. And so, as Peggy delineated, the University has put a lot of resources, money, people, and programming into these areas.Responses to the first survey also showed the need to change the culture on campus. We can’t just work on our response to incidences of sexual and gender-based harassment and misconduct. We also need to reduce instances of this conduct happening in the first place. It’s important that not just our students but also our faculty and staff are aware of ways in which our culture is allowing Harvard to be a place where sexual and gender harassment are seen as somehow possible. In organizations, cultural messages about gender come from the makeup of leadership teams. At Harvard, Presidents Drew Faust and Larry Bacow have continued to appoint a more diverse set of leaders, including exemplary female role models, to this end. It’s a mistake to think that ‘This issue doesn’t apply to me,’ or that ‘I can’t make a difference.’ It matters for all of us, as a community, and I can assure the members of Harvard’s community who complete the survey that we will take their responses seriously and react in accordance with what we learn.I recognize how busy all of us are, especially this time of year, but, by committing to completing this survey, our students are participating in the collective process of making Harvard a safer, healthier, more inclusive place to be. I’m grateful for all of their valued time and input.All degree-seeking candidates at Harvard are encouraged to take The Harvard Student Survey on Sexual Assault & Misconduct. Survey responses are completely confidential.
In light of recent focus on the Latino vote as the 2014 midterm elections approach, Notre Dame hosted a panel discussion Wednesday evening in McKenna Hall entitled, “American Politics in the 21st Century: The Latino Vote and the 2014 Elections.”Christina Wolbrecht, associate professor of political science at Notre Dame, moderated the three-person panel. Panelists included professor of American politics Ricardo Ramirez, professor Michael Jones-Correa of government from Cornell University and professor of political science Sophia Wallace from Rutgers University.Ramirez spoke first, asking why the Latino vote is suddenly receiving so much attention.In response to his own questions, he said, “We have to look at the dramatic increase. In the period between 1991 and 2011 more than a third of the new 13 million U.S. citizens were Latinos, you had a dramatic increase in the number of 18-24 year old Latinos between 1991-2006.“There’s almost as many Latino voters… to potential Latino voters.”Jones-Correa said the Latino vote matters because these new voters have the possibility of swaying an outcome of an election.“When you have new residents moving into the states will they maintain their own political orientation or create a shift?” he said.There are three ideas around this question, Jones-Correa said. One, because Latinos tend to vote liberally, they will sway the states they move to. Two, Latinos will move to states that match their ideology, and three, Latinos will be influenced by the people around them and may even be swayed themselves to vote conservatively, he said.Jones-Correa said many first generation Latinos likely to claim no party affiliation and be more influenced by their neighbors because they want to integrate into American society or because they do not understand the mission of each party.Wallace continued this thought and asked what the most important issues are for the Latino voter.“[Immigration] has become increasingly an extremely important issue in the Latino community, but it’s also affecting turn out and affecting vote choice and that is both mobilizing Latino voters for democratic candidates as well as mobilizing them against Republicans in specific places,” Wallace said.Wallace said the Latino vote is more important than many American citizens make it out to be. The U.S. should care about the Latino vote, Wallace said, because it has the potential to increase the number of Latino elected officials, mobilize politicians to respond to Latino issues, and moderate campaign ads for immigration.Wallace also said we observe a two-to-one ratio in favor of Democrats.“Both parties are trying to craft specific campaign strategies to mobilize Latinos, but a lot of this hinges on the handling of immigration as an issue.”Wallace said the GOP runs the risk of alienating Latino voters with very conservative viewpoints.Tags: Latino politics, McKenna Hall
Tuareg rebels in northern Mali attacked the positions of a pro-government militia on Monday, in fighting that is undermining government attempts to pacify the region, sources from both groups said.Secessionist Tuaregs signed a peace agreement in June that Western countries, including France, hope will allow the Malian army to focus on stamping out Islamist groups, some of them linked to al-Qaeda.But tensions have been rising again, and neighbouring Niger is due to host talks to ease the situation on Wednesday.A spokesperson for the Platform, an alliance of pro-government groups, said fighters from the Tuareg Co-ordination of Azawad Movements (CMA) had attacked two Platform positions in the early morning, in the third day of clashes. “I think that they are looking for a pretext to boycott the meeting in Niamey by saying there are clashes in the north,” said Fahad Ag Almahamoud, a leader of the Gatia militia, which belongs to the Platform.
Florida’s average gasoline price has dropped making it the leading state for affordable gas. Gas prices are down to 22 cents a gallon, according to the American Automobile Association (AAA). Florida drivers are now paying on average, $2.57 per gallon.The AAA says the decreased price in gas stems from the drop in prices of crude and wholesale gasoline. As of Monday, Florida gas prices averaged $2.56. The U.S. average was $2.81.