This document summarizes research on the enterovirus strain EV-D68 and its ability to cause respiratory illness in children. The key points are: 1) EV-D68 typically causes mild cold symptoms but in some cases can lead to wheezing and difficulty breathing as it affects the lower respiratory tract. 2) Studies are being conducted to understand why this strain may be causing more severe illness and if there are any genetic differences from past strains. 3) While most children recover on their own, those with underlying conditions like asthma are at higher risk and parents should seek medical care if their child's breathing becomes labored.

1. Pharmacology
By:
Lontoc, Shelah Mae H.
BSMLS III-D
For:
Mr. Anastacio F. Mendizabal Jr., RN, MAN
Professor

2. Respiratory
System
Pharmacology

3. Latest Enterovirus Strain Can Cause Respiratory Problems In Children
TORONTO -- The cold-causing bug, enterovirus D68, that's been making some children
severely ill across the U.S. and now in parts of Canada has been around for decades, but
doctors acknowledge there may be something different about the strain circulating this year.
The virus -- also known as EV-D68 -- tends to cause symptoms in the lower part of the
respiratory system, putting children with asthma or wheezing at greater risk of developing more
acute illness from the infection; most cold viruses typically affect the upper airways.
"At this time, we don't know why this virus has a predilection for the lower respiratory tract, why
it's causing more severe respiratory illness," said Dr. Danuta Skowronski, an infectious diseases
specialist the BC Centre for Disease Control.
"Those sort of secrets have yet to be found out," she said Monday from Vancouver, noting that
studies need to be completed on EV-D68's genetic profile to tease out anything that might be
unique to the strain.
There are more than 100 enteroviruses, the second most common cause of the common cold
after rhinoviruses. But Skowronski said EV-D68 acts more like a rhinovirus than an enterovirus -
- it doesn't replicate in the acid-rich environment of the gastrointestinal tract and prefers
temperatures around 33 C, unlike its namesake cousins.
EV-D68 typically starts with garden-variety cold symptoms -- runny nose, sneezing and
coughing -- and most children infected with the virus have mild to moderate symptoms that
resolve on their own.But in some cases, the lower airways become compromised, leading to
wheezing and difficulty breathing that requires prompt action, doctors advise parents. "Certainly,
if their children are developing signs of respiratory distress, with more laboured breathing, more
rapid breathing, losing their appetite, then they really should be seeking medical attention,
particularly going to the emergency department," said Dr. Upton Allen, chief of infectious
diseases at Toronto's Hospital for Sick Children.
While there is no direct treatment against the virus, children may receive medications to ease
airway constriction and be admitted to a ward for observation.
"The ones that come to hospital generally represent the more severe end of the spectrum,"
Allen said. "If they are among the most severely ill who require help with their breathing, then
they would be admitted to an intensive care unit where they get ventilated."
As of Friday, the U.S. Centers for Disease Control said there were 160 confirmed cases of EV-D68
in 22 states, with many more possible or suspected cases being investigated.

4. Sick Kids recently admitted a dozen children to the ICU and all were on ventilators to help them
breathe. But results of testing released Monday showed only one of the young patients was
infected with enterovirus D68. The others had respiratory infections caused by other common
cold viruses. The patient with EV-D68 has recovered and been discharged home, a
spokeswoman said.
In B.C., Skowronski said there have been seven lab-confirmed cases of EV-D68, four in children
aged under 10 and three aged between 10 and 19.
It's difficult to say how common it is for EV-D68 to send a child to the ICU and treatment with a
ventilator. Most children who come down with a respiratory illness, even if they end up in the
ER, aren't tested to see what virus is causing their infection, she said.
In previous EV-D68 outbreaks -- there were at least six between 2008 and 2010 -- about 20 per
cent of the 100 cases described in the medical literature required ICU admission, Skowronski
said. In Kansas City in mid-August, where the current outbreak was first identified, all of 19
confirmed cases were admitted to the ICU, while 90 per cent of the 11 cases in Chicago were
given intensive care.
"Since we don't test everyone for enterovirus when they have symptoms, mild symptoms for
instance, it may be that all of our surveillance is being skewed towards the more severe end of
the spectrum," Skowronski said. "And children may be having more severe symptoms because
of the combination of lack of immunity and smaller airways."
Immunity is a key issue: enterovirus D68 was first identified in 1962, and it may be that young
children are more susceptible to the bug than adults because they have not been exposed to
the virus before and therefore have no antibodies to fight it off.
That doesn't mean that adults can't contract EV-D68, said Allen, and those with existing lung
diseases such as COPD could be at risk for more severe symptoms.
"It really is children with underlying conditions, and in particular those who have a history of
asthma or wheezing, who are having the most difficult time with this virus," said Skowronski.
"So children who have that history, if they do develop a respiratory illness and it's worsening,
with difficulty breathing, (parents) should seek medical care promptly or urgently, without delay
in order to get the supportive care needed," she said, stressing that parents should trust their
instincts. Otherwise, kids should be kept home from school and get lots of rest and fluids until
symptoms abate. "That is likely all that is needed for the vast majority," she said, adding that
frequent hand-washing and other infection-control measures should be practised to prevent
transmission of the virus to others.

5. Although EV-D68 caused three deaths in previous outbreaks, Allen said dying is not a "major
feature" of the disease, and that if a patient were to sadly die, it "would not necessarily indicate
a worsening of the outbreak, because that type of scenario can happen in any year."
To put the summer-fall spate of cases in context, Skowronski said enteroviruses generally pale
in comparison with such respiratory microbes as, say, seasonal influenza, which kills thousands
around the world each year, especially among the very young and very old.
"In part, we've created a scenario of outbreak by virtue of our diagnostic testing, both in terms of
who we're testing and how we're testing that may have created this sense of alarm that's
somewhat artificial," she said of widespread news reports on the outbreak.
"Having said that, since we have recognized this and since there are certain people who may be
at higher risk, we ought to profit from that information and make sure that they get the care that
they need. "But the sky is not falling."
Read more: http://www.ctvnews.ca/health/latest-enterovirus-strain-can-cause-respiratory-problems-
in-children-1.2019137#ixzz3EEVQ72Xq
NEWLY APPROVED DRUGS
Arnuity Ellipta (fluticasone furoate inhalation powder); GlaxoSmithKline; For the treatment of
asthma, Approved August 2014
Grastek (Timothy Grass Pollen Allergen Extract); Merck; For the treatment of grass pollen-induced
allergic rhinitis, Approved April 2014
Incruse Ellipta (umeclidinium inhalation powder); GlaxoSmithKline; For the treatment of chronic
obstructive pulmonary disease, Approved May 2014
Oralair (Sweet Vernal, Orchard, Perennial Rye, Timothy and Kentucky Blue Grass Mixed
Pollens Allergen Extract); Greer Labs; For the treatment of grass pollen-induced allergic rhinitis
with or without conjunctivitis, Approved April 2014
Ragwitek (Short Ragweed Pollen Allergen Extract); Merck; For the treatment of short ragweed
pollen-induced allergic rhinitis, Approved April 2014
Striverdi Respimat (olodaterol); Boehringer Ingelheim; For the treatment of chronic obstructive
pulmonary disease , Approved July 2014
Zykadia (ceritinib); Novartis; For the treatment of ALK+ metastatic non-small cell lung cancer,
Approved April 2014

6. Digestive System
Pharmacology

7. Breast Milk Can Reduce Risk of Gastrointestinal Diseases
By Amy Jacob | September 10, 2014
Breast feeding can potentially protect premature babies from a toxic gastrointestinal disease,
according to a recent study published in in the American Journal of Pathology.
Researchers from the Saban Research Institute at the Children’s Hospital, Los
Angeles discovered that the protein neuregulin-4 (NRG4), which exists in breast milk but is not
found in baby formula, has positive effects on protecting newborns from the debilitating
intestinal disease, necrotizing enterocolitis (NEC).
Breast feeding has long been lauded a more favorable alternative to formula feeding. The
natural milk comprises of a reservoir of antibodies, carbohydrates, fats, and proteins, all
required to provide effective care while battling infections.
Prior research has reported that while 30% of babies with NEC can die, NEC survivors must
deal with a lifetime of serious consequences like missing parts of their intestines or even submit
to consistent intravenous nutrition. As NEC is prevalent among premature infants, reports have
surmised underdeveloped intestines to be the prime suspect, as the slightest intestinal injury
could cause a tear, providing the outlet for waste matter to escape to the blood stream.
The study’s leader, Mark Fey, PhD,said, “Our research suggests that without the NRG4 protein
found in breast milk, a normal protection mechanism, for the immature gut may be missing. If a
baby on formula encounters an NEC trigger such as intestinal infection or injury, he or she may
be at increased risk for a life-threatening condition.”
In a series of tests observing rodent models, conducting in vitro analysis, and examining
intestinal tissue of infants, experts discovered the NRG4 works by directly latching onto an
intestinal receptor, ErbB4, to effectively combat inflammations resulting from intestinal
damage.Mice that were administered a combination of the baby formula and NRG4 protein
responded positively, receiving the anticipated protection against NEC.
Fey commented in a news release, "We're finding a protective protein in breast milk, with its
receptor in the intestine. Given that NEC is a significant clinical problem without an effective
treatment, we plan to evaluate NRG4 for its therapeutic potential in this disease."
See more at: http://www.hcplive.com/articles/Breast-Milk-Can-Reduce-Risk-of-Gastrointestinal-
Diseases#sthash.G2VbCJJ6.dpuf

8. Transnasal Endoscopy To Go?
Chicago—Food trucks are all the rage. So why not appeal to the anatomy a little higher up in
the gastrointestinal tract?
New studies suggest that transnasal endoscopy (TNE) could become more acceptable as a
screening tool for Barrett’s esophagus (BE), thanks to recent technological advances that have
improved the portability of the procedure.
One study looked at the feasibility of screening with TNE in a van set up as a mobile research
unit. Another, using the same patient data, demonstrated that substantial rates of BE can be
identified in patients with obesity whether or not they complain of symptoms of
gastroesophageal reflux (GERD).
TNE, which can be performed without sedation, is already widespread, but renewed interest in
this technique as a screening tool is being driven by the development of smaller units with
disposable sheaths. The sheaths, which prevent contact between the scope and the patient to
circumvent the need for scope sterilization, greatly facilitate portable units.
Both new studies were presented by investigators at Mayo Clinic, in Rochester, Minn., at
Digestive Disease Week 2014 (DDW). Prasad G. Iyer, MD, a consultant in the Barrett’s
Esophagus Unit in the Division of Gastroenterology and Hepatology at Mayo, led the work.
Study participants were recruited from a sample of residents 50 years of age or older from
Olmsted County, the home of the Mayo Clinic, who completed a questionnaire on
gastrointestinal (GI) symptoms. Of an initial cohort of 459 patients, 209 agreed to undergo
screening for BE. The patients were randomized to conventional sedated endoscopy,
unsedated TNE performed in a clinic setting and unsedated TNE performed in a mobile unit.
In a feasibility study (abstract 160), the primary outcome was participation, said Sarmed S.
Sami, MD, of Mayo’s Division of Gastroenterology and Hepatology and the Nottingham
Digestive Diseases NIHR Biomedical Research Unit, in the United Kingdom. Rates of
participation did not differ significantly among the three groups, ranging from about 41% to 48%.
Independent of endoscopy type, the presence of frequent GERD symptoms was associated with
a threefold increase in screening participation.
Although the quality of the endoscopic examination was judged to be similar in the three groups,
biopsy rates were 80% for TNE compared with 100% for sedated endoscopy. According to the
researchers, some patients could not tolerate the TNE with a biopsy channel, thus explaining
the lower biopsy rates in the TNE group.
Unsedated TNE was associated with shorter procedure times. Patients who underwent sedated
endoscopy reported less discomfort, but unsedated TNE was generally well tolerated, and
approximately 80% of patients who underwent the procedure said they would be willing to do so
again in the future.
Although the results of this study suggest that outpatient TNE, including mobile, “may be a
feasible alternative to sedated endoscopy” for BE screening, the second study elaborated why
easier, more cost-effective screening tools are needed (abstract 105). In this evaluation of the
same population, presented by Nicholas R. Crews, MD, a fellow in Mayo’s Division of

9. Gastroenterology and Hepatology, the prevalence of BE in the 33% of patients with GER
symptoms on questionnaires was compared with the 67% without GER symptoms.
The BE prevalence was 8.7% for those with GER versus 7.9% for those without, a difference
that did not reach statistical significance. In these subgroups, the mean length of the BE
segment also did not differ. Regardless of GER, those with BE were more likely to be men, to
exhibit central obesity and to consume more than two alcoholic beverages per day.
“This directly challenges the established GER-based screening paradigm for BE and provides
strong rationale for using central obesity in Caucasian males, with or without GER, as a criterion
for screening,” Dr. Crews said.
Joel Richter, MD, director of the Division of Digestive Diseases and Nutrition at the University of
South Florida, in Tampa, said TNE “may be the best screening tool for asymptomatic patients
who are well educated and informed.” However, Dr. Richter said, “in the real world, most
patients prefer to be put to sleep.”
Dr. Richter also noted that optimal biopsies, which are more consistently obtained with a
conventional scope, are required for patients with BE.
“Maybe when reimbursement becomes higher for transnasal endoscopy than for standard
endoscopy with propofol sedation, transnasal endoscopy will be better utilized,” Dr. Richter
observed. Without this incentive, he predicted that the current “dope-and- scope” approach will
prevail at most centers.
Why You Shouldn't Drink Warm Bottled Water
A few years back, rumors circulated that Sheryl Crow claimed drinking bottled water left in a
hot car had given her breast cancer. The result? A fresh wave of good, old-fashioned
American fear. Since then, the worry over plastic bottles leaching dangerous chemicals into
our water has never quite disappeared — and perhaps for good reason, suggests a new
study published in the September edition of Environmental Pollution.
Scientists from Nanjing University in China and the University of Florida investigated the
effects of storing 16 brands of bottled water (all sold in China) at three temperatures: 39
degrees F, 77 degrees F, and 158 degrees F, intended to mimic the temperatures of a
refrigerator, a standard room, and the inside of a car, respectively. “Based on the literature,
that is a temperature that’s reachable on a hot summer day in a car,” study author Lena Ma
told Yahoo Health.
The researchers checked the levels of two substances —antimony and bisphenol A (BPA) —
after one, two, and four weeks. Antimony, a trace heavy metal, has been found to play a role
in lung, heart, and gastrointestinal diseases, according to a 2009 study review. The
International Agency for Research on Cancer classifies one form of the metal, called
antimony trioxide, as a “possible carcinogen.” BPA, meanwhile, is a chemical that can mimic
estrogen in the body and which is found in some plastics; it’s been banned for use by the
FDA in baby bottles and sippy cups.

10. The researchers found that as the temperature rose and time passed, increasingly high
levels of antimony were detectable in the bottles of water. Specifically, at 77° F, the release
of antimony increased by as much as twofold over that at the cooler temperature — although
the levels of the trace metal varied by brand, increasing significantly at 77 degrees F in only
six out of 16 brands.
BPA levels, meanwhile, went up in only three brands at this temperature, though the
concentration still wasn’t high enough to cause concern, Ma said. But the presence of BPA in
bottled water, period, is still something of a mystery: “In theory, the plastic should not contain
BPA,” she said. One explanation, she noted, is that “during the manufacturing process,
especially if you use recycled plastics, you may find trace amounts of BPA. It’s an impurity.”
At 158 degrees F — the hot-car condition — antimony concentrations consistently increased,
with up to a 319-fold boost in levels of the metal, compared with levels in the refrigerator
condition. The highest level measured was .00026 milligrams per liter of water, which is still
lower than the EPA’s legal limit of .0006 milligrams per liter for drinking water. However,
other countries, such as Japan, have set stricter limits on the substance.
The scientists estimate that, worst-case scenario, drinking the most heavily contaminated
brand of bottled water could mean consuming .0004 mg of antimony per kilogram of body
weight each day, which they said may pose a health risk, especially for children. Another
factor to consider: Calcium — often found in bottled mineral water — has been shown to
enhance the release of antimony. “Therefore,” the researchers wrote, “the health risk caused
by [antimony] release from PET bottles in this study may be underestimated.”
Why is antimony even in plastic bottles? The trace metal is necessary for the manufacture of
polyethylene terephthalate, or PET, the most popular material for food and beverage
packaging. Although the bottled water in the study was from China, “in the U.S., you also
have antimony in the plastic,” said Ma. “But I cannot say that what you find in China is what
you’re going to find in the U.S.” Past research has, in fact, shown variability in the quality of
PET plastics from different countries.
Despite the relatively low levels of the substances studied, Ma still advises tossing — rather
than drinking — water that’s been stored in hot conditions. “If you have bottled water in a hot
temperature, the antimony will release from the plastic and get into your water,” she said. Her
advice: Store your 24-pack of bottled water in a refrigerator or in room-temperature
conditions.
Should you worry about one quick swig of warmed-up water? “If you drink [a hot bottle of
water] once in a while, I don’t think that’s a concern. One is no problem. Even a few is no
problem. It’s cumulative, ” Ma told Yahoo Health. “I don’t want to mislead people, saying
bottled water is not safe. Bottled water is fine. You can drink it — just don’t leave it in a hot
temperature for a long time. I think that’s the important message.”

11. NEWLY APPROVED DRUGS
Cyramza (ramucirumab); Eli Lilly; For the treatment of gastric cancer, Approved April 2014
Entyvio (vedolizumab); Millenium Pharmaceuticals; For the treatment of adults with ulcerative
colitis and Crohn's disease, Approved May of 2014
Cerdelga (eliglustat); Genzyme; For the treatment of certain adult patients with Gaucher disease
type 1, Approved August 2014
Simponi (golimumab); Janssen Biotech; For the treatment of ulcerative colitis, Aproved May
2013
Stivarga (regorafenib); Bayer; For the treatment of gastrointestinal stromal tumor, Approved
February 2013
Uceris (budesonide); Santarus; For the treatment of ulcerative colitis, Approved January 2013
After 20 years without any new therapies to treat hepatitis C virus (HCV) infection, 2 new drugs
were approved in May by the US Food and Drug Administration (FDA). Telaprevir (Incivek®;
Vertex; Cambridge, Massachusetts) was approved May 23 for the treatment of chronic hepatitis
C genotype 1 infection, in combination with peginterferon alfa and ribavirin, in patients 18 years
of age and older with compensated liver disease, including cirrhosis, who are treatment-naive or
who have been treated previously with interferon-based treatment.
Boceprevir (Victrelis™) was approved by the FDA on May 13 for the treatment of HCV, in
combination with peginterferon alfa and ribavirin, in patients 18 years of age and older with
compensated liver disease, including cirrhosis, who are previously untreated or who have failed
previous interferon and ribavirin therapy.
On April 29, the FDA approved injectable esomeprazole sodium (NexiumIV®; AstraZeneca;
Wilmington, Delaware) as a new short-term treatment option for children with gastroesophageal
reflux disease (GERD) with erosive esophagitis. It is the first proton-pump inhibitor (PPI)
approved for use in infants younger than 1 year old.
The FDA updated the label for natalizumab (Tysabri®; Biogen Idec; Weston, Massachusetts) on
April 22 to further quantify the risk for progressive multifocal leukoencephalopathy in patients
taking the drug. The new label also expands the existing precautions for patients using
concomitant immunosuppressive medications to include previous use of such agents.
The FDA issued a safety alert April 15 about the risks of administering lansoprazole (generic;
Teva Pharmaceuticals; Petach Tikva) via oral syringe or feeding tube. The orally disintegrating
tablet formulations of the drug are sometimes administered as suspensions, but particles may
clump together and block the flow of liquid through gastric tubes. The branded formulation of
lansoprazole (Prevacid® SoluTab, Takeda Pharmaceuticals; Osaka, Japan) was not implicated
directly in the FDA announcement.
A neurostimulator was approved March 14 to treat fecal incontinence that is unresponsive to
conservative therapy. The InterStim® Therapy System, made by Medtronic Inc of Minneapolis,
Minnesota, is a surgically implanted device that delivers electrical impulses to the sacral nerve,
allowing for activation or inhibition of effector organs that the sacral nerves innervate, such as

12. the anal sphincter, pelvic floor, and rectosigmoid colon. The device was already approved for
the treatment of urinary urge incontinence.
The Xpert® C difficile Epi, made by Cepheid of Sunnyvale, California, was cleared by the FDA
April 8 as a rapid diagnostic test for Clostridium difficile infection. In addition to detecting the
toxin B gene associated with C difficile infection in a patient's stool, the new test also identifies
the epidemic strain 027/NAP1/BI, which is associated with a greater incidence and severity of
CDI infection.
On March 23, the FDA removed a label warning on over-the-counter PPIs, saying that the risk
of osteoporosis and fracture was unlikely with the low-dose version and short-term use of these
medications. The prescription versions of PPIs, which include omeprazole (Prilosec®,
Zegerid®), will continue to bear the label warning.
The FDA granted orphan drug designation in January for all formulations of fidaxomicin
(Optimer Pharmaceuticals, Inc; San Diego, California) for the treatment of CDI in pediatric
patients aged 16 years and younger. Fidaxomicin is a first-in-class, narrow-spectrum
macrocyclic antibiotic that acts by inhibiting RNA polymerase, selectively eradicating C difficile
with minimal disruption of normal intestinal flora.

13. Endocrine System
Pharmacology

14. A Genetic Form Of Deafness Is Due To Absence Of Thyroid Hormone
Fatigue, weight gain, chills, hair loss, anxiety, excessive perspiration - these symptoms are a
few of the signs that the thyroid gland, which regulates the body's heart rate and plays a crucial
role in its metabolism, has gone haywire. Now, new research from Tel Aviv University points to
an additional complication caused by thyroid imbalance: congenital deafness.
The study, published in Mammalian Genome, was conducted by Prof. Karen B. Avraham and
Dr. Amiel Dror of the Department of Human Molecular Genetics and Biochemistry at TAU's
Sackler School of Medicine. Using state-of-the-art imaging, the researchers found that
congenital deafness can be caused by an absence of a thyroid hormone during development.
"Since our laboratory mainly focuses on the system of the inner ear, the study of a system such
as the thyroid gland was new to us and therefore challenging," said Dr. Dror. "My curiosity as to
how these two systems interact together to develop normal hearing led to this multidisciplinary
study."
A colorful approach
The researchers used mouse populations to study a form of congenital deafness that affects
humans. Harnessing electron microscopy at the Sackler Cellular & Molecular Imaging Center,
researchers tracked the inner hair cells of the cochlea (the auditory portion of the inner ear) in
two groups - control (wild) mice and mutant (congenitally deaf) mice. Inner-ear hair bundles in
the affected mice were labelled with bright colors to highlight the disorganization of the ear's hair
cells.
Examination of the inner ear showed a spectrum of structural and molecular defects consistent
with hypothyroidismor disrupted thyroid hormone action. The researchers' analysis of the
images revealed defective formation of the mice's thyroid glands: labelled thyroid follicles did
not grow or grew incompletely.
"Our work demonstrated that normal hearing fails to develop when thyroid hormone availability
is insufficient as a result of a genetic mutation," said Dr. Dror. "Our model provides a platform to
test therapeutic approaches in order to prevent hearing loss before it occurs. There is still long
way ahead before we get to the point of practical treatments with our research, but we believe
we are moving in the right direction."
A lifelong commitment
"My attraction to sound began very early as a child," said Dr. Dror. "I play string instruments and
pay great attention to sound quality and perception. As a graduate student in the Avraham
laboratory, I was exposed to the fascinating world of genetics and the opportunity to combine
two fields of research that I am interested in: genetics and hearing. Now that I have continued
this research as a medical student, the direct interaction with patients with hearing impairments
encouraged me to explore the clinical significance of my research."
As a physician, Dr. Dror believes it is important to pursue research with clinical consequences
for his patients. "The basis of all advanced medicine relies on both basic science and clinical
research. I hope that our study will contribute a modest part to global efforts for improved
medical care and treatment of hearing impairments," Dr. Dror said.
Role of hormone in patient responses to ovarian cancer treatment
Researchers at Women & Infants Hospital of Rhode Island recently published the results of an
investigation into how we might better tailor therapy for ovarian cancer.

15. The work comes out of the molecular therapeutic laboratory directed by Richard G. Moore, MD,
of Women & Infants' Program in Women's Oncology. Entitled "HE4 expression is associated
with hormonal elements and mediated by importin-dependent nuclear translocation," the
research was recently published in the international science journalScientific Reports, a Nature
publishing group.
The goal of the study was to investigate the role of the hormone HE4 in modulating an ovarian
cancer's response to hormones and hormonal therapies. HE4 is a biomarker that is elevated in
ovarian cancer and is known to play a role in resistance to chemotherapy.
"There is little known about the biologic functions of HE4 but we did know that there were
hormonal responsive elements within the promoter region of the HE4 gene, which regulates
gene expression. For this reason, we hypothesized that steroid hormones could influence
expression of HE4 in ovarian cancer," Moore explains.
The study resulted in multiple findings:
 Hormonal therapies like Tamoxifen and Fulvestrant are effective because they bind
the estrogen receptor. If cells have less estrogen receptor expression, these drugs can't do
their job. This, the researchers believe, is due to epigenetic modifications which modify the
DNA structure but not the DNA sequence itself. Overexpression led to the epigenetic
modification known as decreased DNA methylation in cell culture and in human tissue
samples.
 Treatment of ovarian cancer cells with Tamoxifen and Fulvestrant all cause HE4 to
translocate to the nucleaus, where it can then effect further gene expression in cancer cells.
 Using the drug Ivermectin, the researchers were able to inhibit the protein import in-4, which
then inhibited HE4 from translocating to the nucleus. If HE4 can't enter the nucleus, it cannot
affect gene expression. The ability to block HE4 from entering the nucleus restored sensitivity
to hormonal therapy.
"We are not certain but believe this might mean there could be a subset of women whose
tumors are more likely to respond to hormonal therapy. Moreover, we might be able to
eventually identify which tumors these are and target treatment," Moore says.
His lab will continue to investigate the expression of estrogen receptors in both primary and
recurrent ovarian cancers and how that relates to HE4 expression. In addition, he and other
researchers will investigate how importin inhibitors may play a role in addressing
chemoresistance to standard therapeutics, particularly in HE4 overexpressing tumors.

16. Endocrine-related protein found to be master regulator in other important diseases
Investigating a protein known to be involved in regulating human glucose levels, genomic
scientists found that this factor has a broader reach than first thought, acting on key gene
pathways involved in cardiovascular, neuropsychiatric, and cancer-related diseases, in addition
to its role in endocrine traits.
"We found strong evidence that this protein family, FOXA2, is a master regulator of genetically
vulnerable pathways in multiple diseases," said study leader Struan F.A. Grant, Ph.D., a
genomics expert and holder of the Daniel B. Burke Chair for Diabetes Research at The
Children's Hospital of Philadelphia. Further study of those pathways may point the way to
various novel therapies.
Grant and colleagues published their study online in The Journal of Clinical Endocrinology &
Metabolism.
This computational analysis leveraged data from a team led by co-author Klaus H. Kaestner,
Ph.D., of the Perelman School of Medicine at the University of Pennsylvania, and used two
important tools of next-generation genomic analysis: chromatin immunoprecipitation and
massively parallel sequencing, together abbreviated as ChIP-seq. Relying on the fact that gene-regulating
proteins such as transcription factors bind to DNA, ChIP-seq isolates the pieces of
DNA that are bound by a particular protein.
Researchers then pass those fragments through automated sequencing machines to pinpoint
and inventory the regions of the genome that specific transcription factors occupy. This
knowledge allows investigators to better understand how transcription factors may activate or
repress genes along important biological networks.
Grant has long studied genetics of diabetes and obesity, and in 2006 discovered the gene
region with the strongest known effect on type 2 diabetes. In the current study, the Grant and
Kaestner teams focused on the Forkhead Box A transcription factor, referred to as FOXA2.
Because FOXA2 was already known to act in the liver in affecting glucose levels, Grant and
colleagues started with the hypothesis that FOXA2 regulated molecular pathways important in
endocrine biology.
As they performed their analyses, the researchers found that FOXA2 proteins acted on sites in
the genome that contained genes affecting endocrine-related traits such as glycemic levels,
although not type 2 diabetes. They also found strong genome occupancy patterns associated
with cardiovascular traits such as lipid levels, as well as with neuropsychiatric traits and cancer.
"FOXA2 appears to function as a master regulator for over a hundred other transcription factors,
so it may play an outsized role in human health and disease," said Grant. He added that many
of these other transcription factors may in turn be fruitful candidates for researchers
investigating disease pathways, and ultimately may allow scientists to discover targets for
potential new treatments.

17. NEWLY APPROVED DRUGS
Afrezza (insulin human) Inhalation Powder; Mannkind; For the treatment of diabetes mellitus,
Approved June 2014
Aveed (testosterone undecanoate) injection; Endo Pharmaceuticals; For the treatment of
hypogonadism, Approved March 2014
Farxiga (dapagliflozin); Bristol-Myers Squibb; For the treatment of type II diabetes, January of
2014
Jardiance (empagliflozin) ; Boehringer Ingelheim; For the treatment of type II diabetes,
Approved August 2014
Natesto, (testosterone) nasal gel; Trimel Pharmaceuticals; For the treatment of deficiency or
absence of endogenous testosterone, Approved May 2014
Tanzeum (albiglutide); GlaxoSmithKline; For the treatment of type II diabetes mellitus, Approved
April 2014
Vogelxo (testosterone) gel; Upsher-Smith; For males with a deficiency or absence of
endogenous testosterone, Approved June 2014
Brisdelle (low-dose paroxetine mesylate); Noven Pharmaceuticals; For the treatment of
vasomotor symptoms of menopause, Approved July 2013
Duavee (conjugated estrogens/bazedoxifene); Pfizer; For the treatment of vasomotor symptoms
associated with menopause and postmenopausal osteoporosis, Approved October 2013
Invokana (canagliflozin); Janssen Pharmaceuticals; For the treatment of type II diabetes
mellitus, Approved April 2013
Nesina (alogliptin); Takeda; For the treatment of type II diabetes mellitus, Approved January
2013
Osphena (ospemifene); Shionogi; For the treatment of dyspareunia and vulvar and vaginal
atrophy due to menopause, Approved March 2013
Mifepristone (Korlym™, Corcept Therapeutics Incorporated, Menlo Park, California) was
approved to manage hyperglycemia in patients with endogenous Cushing's syndrome and type
2 diabetes mellitus or glucose intolerance who are not candidates for surgery or in whom
surgical treatment has failed. This cortisol receptor blocker has potent antiprogestational
properties and should never be used in pregnant women due to risk for pregnancy termination.
Pregnancy must be excluded in women of reproductive age prior to initiation of therapy or if
treatment is interrupted for more than 14 days. The manufacturer will distribute Korlym through
a central pharmacy; retail pharmacies are unlikely to supply this drug adequately due to the rare
nature of the condition.
The FDA changed the pregnancy category for insulin detemir (rDNA origin) injection (Levemir®,
NovoNordisk A/S, Bagsvaerd, Denmark ) from C to B. No increased fetal risk was found in a
randomized controlled trial of pregnant women with type 1 diabetes mellitus who were taking
Levemir during pregnancy.

18. The FDA has approved a once-weekly, extended-release formulation of exenatide injection
(Bydureon™, Amylin Pharmaceuticals, Inc., San Diego, California). This glucagon-like peptide-1
receptor agonist is indicated as an adjunct to diet and exercise in adult patients with type 2
diabetes mellitus (DM) and is administered subcutaneously once every 7 days. Bydureon is not
recommended as first-line therapy and should not be used to treat type 1 DM or diabetic
ketoacidosis. Use with insulin and in patients with a history of pancreatitis is not recommended.
A Risk Evaluation and Mitigation Strategy (REMS) is required with Bydureon to help ensure that
the benefits outweigh the risks for medullary thyroid carcinoma and acute pancreatitis.
The FDA approved a combination of the dipeptidyl peptidase-4 (DPP-4) inhibitor linagliptin and
biguanide metformin hydrochloride (Jentadueto™, Boehringer Ingelheim Pharmaceuticals, Inc.,
Ridgefield, Connecticut; and Eli Lilly and Company, Indianapolis, Indiana) as an adjunct to diet
and exercise in adult patients with type 2 DM. Jentadueto should be given twice daily with
meals, using slow dose escalation to decrease the adverse gastrointestinal effects associated
with metformin. Jentadueto should not be used for type 1 DM or diabetic ketoacidosis, and use
has not been evaluated in combination with insulin. Labeling contains a black box warning about
the risk for lactic acidosis associated with metformin accumulation.
Once-daily Janumet® XR (Merck & Co., Inc, Whitehouse Station, New Jersey) was approved by
the FDA for adjunct management of type 2 DM in combination with diet and exercise in adults.
Janumet XR is the combination of the DPP-4 inhibitor sitagliptin and extended-release
metformin. Janumet XR is not indicated for type 1 DM or diabetic ketoacidosis and has not been
evaluated in patients with a history of pancreatitis. To decrease the adverse gastrointestinal
effects of metformin, administration with the evening meal is preferred, and dosing should be
gradually escalated. Labeling contains a black box warning regarding the risk for lactic acidosis
associated with metformin accumulation. Decrease of insulin or insulin secretagogue (eg,
sulfonylurea) dose requirements may be needed with concomitant use of Janumet XR to
minimize risk for hypoglycemia
The first remote glucose monitor (mySentry™, Medtronic, Inc., Northridge, California) was
approved by the FDA. This device allows parents to monitor blood glucose in a sleeping child
with diabetes, even when that child is in another room. This monitor works with the Medtronic
insulin pump, MiniMed Paradigm® REAL-Time Revel™ System..