Category Archives: Biochemistry

Kara Murphy| For the Erie Times-News

Ashley Russell was stuck in traffic on Interstate 295 outsideBaltimore on a November day in 2019. She had finished her day as a post-doctoral research fellow at John Hopkins University and was talking to her parents in Erie on the phone to pass the time during the long drive home.

"It was just a soul-sucking hour-long commute each day," she said. "So I'd usually call my parents, and we'd talk."

2020: Behrend to serve as research partner

That day, her father had news he couldn't wait to share: A $26 million medical research center was coming to Erie. It meant up to 200 good jobs for the region, including two new faculty positions at Penn State Behrend. As Magee-WomenResearch Institute-Erie academic partner for the project, Behrend would create biomedical engineering and biochemistry/molecular biology academic programs.

Russell wanted to return to her hometown but didn't think her career would ever allow it.

"There was nowhere to do biomedical research in Erie," she said. "So I thought there was no way I'd ever live in Erie again."

Now there was not only an opportunity, but it was at Behrend, where she'd earned her undergraduate degree.

2019: $26 million medical research facility coming to Erie

She applied at her alma materand, in August, Russell returned, this timeto stay. Her title at Behrend is now assistant professor of biochemistry and molecular biology.

"Dr. Russell's research is a perfect fit for MWRI-Erie, and for Behrend's increased focus on biochemistry and molecular biology," said Ivor Knight, associate dean for research and graduate studies at Behrend.

Along with teaching, Russell and Jeremiah Keyes the other faculty member brought on at Behrend will lead studies in Behrend's new microbiology labs. Their work will support imaging and cell-growth testing related to MWRI-Erie research.

The larger of the two labs, a $1 million, 2,700-square-foot space in the Advanced Manufacturing and Innovation Center, will become the heart of an advanced imaging facility at Behrend and a resource for start-up companies and products that further Magee Women Research Institute-Erie's studies.

A second, smaller lab will be located in the Otto Behrend Science Building.

The pandemic delayed the new labs' completion, but Russell is hoping to start her first study at Behrend by mid-March. Her first study is looking for biomarkers of chronic stress during pregnancy that might indicate adverse pregnancy outcomes.

"A lot of this work will be done in collaboration with students, which is exciting because undergrad students bring a lot of energy and excitement to the table," she said. "We'll be training them to conduct experiments and how to collect and interpret data."

Knight said he believes Russell's studies will reach beyond Behrend's labs.

"Her study of chronic stress during pregnancy and the properties and behaviors of extracellular vesicles, particularly during the body's immune response, could, over the long term, influence the direction of research for MWRI-Erie, including clinical trials," he said.

Russell is excited about being part of the team building the program from the ground up at Behrend and what MWRI-Erie means for the future of scientific research in Erie.

Community leaders are hopeful as well.

Officials estimated in 2019 when announcing the project that $15 million in new federal research money will flow into Erie during the first five years and that research spending could reach $50 million by the tenth year.

"I believe this is just the beginning that this will open up a lot of opportunities to promote Erie as a biomedical hub for companies," Russell said.

And her commute now? It's 8 minutes.

Kara Murphy is a freelance writer in Erie and publisher of Macaroni Kid Erie. Contact her at murphy_kara@yahoo.com.

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Brain gain: Medical researcher finds her way back to Erie thanks to new research facility - GoErie.com

Laura Van Dorn is a professor at the University of Arizona. She currently teaches chemistry 101A and 101B. CHEM 101A is a general chemistry course and CHEM 101B is an introductory course to organic chemistry and biochemistry. Due to the pandemic, both classes have been switched to a live-online format.

Van Dorn has developed a new, challenging chemistry course: CHEM 130. It is designed to have a year's worth of general chemistry completed in a single semester. CHEM 130 is for students who need the foundations of chemistry and biochemistry, but given their career focus in different areas, will not necessarily go on to take additional chemistry classes. The Daily Wildcat sat down with Van Dorn via email to find out more about the process of starting a new course.

Daily Wildcat: Can you provide a brief description of CHEM 130?

Laura Van Dorn: CHEM 130 will introduce students in nursing and public health majors to the fundamental principles of general and organic chemistry and elements of biochemistry, with a focus on medical, nutritional, and environmental aspects of the discipline.

Current topics in health sciences will be used to guide students in developing a solid background in chemistry that may be applied in their future careers. Critical thinking and pattern recognition will be utilized with the goal of developing skills in problem-solving, applying the foundations of chemistry to new concepts.

Students will be taught to integrate their conceptual and modeling skills with quantitative data to make predictions regarding the behavior of molecules in different environments.

DW: What makes CHEM 130 different from other entry-level chemistry courses?

Van Dorn: CHEM 130 is a one-semester overview of the material, which other chemistry and biochemistry courses typically take several semesters to cover. It is the only course of this kind at UArizona.

It is designed for students who need a fundamental understanding of chemistry and biochemistry, but do not have room in their degree programs for the traditional 2 semesters of General chemistry, two semesters of Organic Chemistry, and two semesters of Biochemistry (which is what Chemistry or Biochemistry majors would normally take).

CHEM 130 will emphasize the elements of chemistry and biochemistry important to public health and nursing fields. It will introduce students to recognizing patterns and making predictions. Demonstrations and activities will be a large part of the course. It can be difficult to visualize some of the concepts in chemistry, thus being able to see the effects of chemicals on different types of matter has the tendency to help students.

DW: Do you recommend those only in the pre-health route to take CHEM 130?

Van Dorn: No, this course is for anyone with an interest in how chemistry applies to every aspect of our lives. Our bodies, our environment, all of it is chemistry.

DW: How would you describe the rigor of this course?

Van Dorn: CHEM 130 will be a challenging class, preparing students for careers in health-related fields. Although no extensive background in math or science will be required before taking the class, students should expect to invest considerable effort in mastering the material. Readings will be assigned before class, and students will complete weekly homework as well as unit assessments.

As the course will be offered in-person and through Arizona Online, students will be able to complete much of the course at their own pace. A three-unit science course does require time outside class, and motivation on the part of the students, but theyll learn some really interesting things.

DW: Is CHEM 130 going to be offered as an alternative for CHEM 151?

Van Dorn: CHEM 130 will be very different from CHEM 151 or its equivalent CHEM 141. CHEM 141 or 151 covers only the first half of General Chemistry. CHEM 130 will encompass all of General Chemistry (i.e. CHEM 141/151 plus CHEM 142/152), in addition to important elements of Organic Chemistry and Biochemistry.

The depths of coverage will, of course, be different, given the course objectives, its target audience, and time constraints, but it is important to stress that CHEM 130 is a much broader class than either CHEM 141 or CHEM 151. CHEM 141 or 151 are suitable for students that need chemistry as a prerequisite for higher-level chemistry classes and have a foundation in math.

DW: Is there anyone else you made and/or designed the class with?

Van Dorn: The course content is my own. I will be working with Celeste Atkins at Arizona Online in order to offer the class online as well as in-person for Fall 2021. Colleen Kelly will be developing the separate lab course, CHEM 130L.

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The future of science education: Q&A with the creator of a new chemistry course - Arizona Daily Wildcat

News releases

February 16, 2021

Two faculty members at the University of Washington have been awarded early-career fellowships from the Alfred P. Sloan Foundation. The new Sloan Fellows, announced Feb. 16, areAshleigh Theberge, an assistant professor in the Department of Chemistry and Jodi Young, an assistant professor in the School of Oceanography.

Open to scholars in eight scientific and technical fields chemistry, computer science, economics, mathematics, molecular biology, neuroscience, ocean sciences and physics the fellowships honor those early-career researchers whose achievements mark them among the next generation of scientific leaders.

The 128 Sloan Fellows for 2021 were selected in coordination with the research community. Candidates are nominated by their peers, and fellows are selected by independent panels of senior scholars based on each candidates research accomplishments, creativity and potential to become a leader in their field. Each fellow will receive $75,000 to apply toward research endeavors.

This years fellows come from 58 institutions across the United States and Canada, spanning fields from evolutionary biology to data science.

Ashleigh Theberge

Theberge is an assistant professor of chemistry. Her research probes the chemical signals that cells use to communicate with one another. The organization of our bodies, with different types of cells taking on discrete functions, depends on this biochemical language.

Were alive because our cells can exchange chemical messages in appropriate ways, said Theberge, who is also an adjunct assistant professor of urology at the UW. All cells human cells, microbes utilize chemical signals to deliver information and influence the properties of other cells.

Jodi Young

Youngis an assistant professor in the School of Oceanography. She studies microbial oceanography, with a focus on the role of marine algae in the carbon cycle. In particular, her research explores polar ecosystems and other extreme environments, and the biochemistry of photosynthesis. Herresearchcombines fieldwork,algal culture manipulationsand biochemical and molecular analyses to uncover the evolution and adaptations of biological carbon fixation in the oceans.

Half of all photosynthesis happens in the oceans, across an amazingly diverse collection of organisms, Young said. My groups research focuses on understanding the underlying physiological and molecular adaptations of marine photosynthesis. Understanding how marine algae have and will adapt to a changing climatereveals insights into how life on Earth evolved and will respond in the future.

For more information, contact Theberge atabt1@uw.edu and Young at youngjn@uw.edu.

Excerpt from:
UW chemist and oceanographer named Sloan Fellows - UW News

Introduction

In 2019, an estimate of global burden of type 2 diabetes mellitus (T2DM) provided by the IDF stood at ~463 million. In 2010, the T2DM burden for 2025 was projected as ~438 million and it has already been surpassed by ~25 million.1 The rise in global T2DM prevalence is a complex amalgamation of development of comorbidities, most common being obesity and depression. It is important to note that prevalence of obesity, depression, and T2DM has increased in parallel at an accelerating rate suggesting interdependencies in the progression of these diseases. Numerous studies indicate the bidirectional associations between T2DM and depression, T2DM and obesity, depression and obesity and the interrelated risks.24 One of the key meta-analyses demonstrated that T2DM/obese patients have a 1.63-fold increased risk of depression in comparison to T2DM alone.5 The disease triad (T2DM, obesity, and depression) has biological pathways overlapping at the level of organs, tissues, cells, and biochemical substrates regulating peripheral and neural metabolism converging at the hypothalamus-pituitary-adrenal (HPA) axis. The HPA axis is central to an individuals response to stressful conditions.68 However, other potential mediators of the obesity-depression association, such as changes in adipokines, have not yet been well explored.8

Depression and T2DM are both known to activate the HPA axis through increased sympathoadrenal system activity.9 There has been mixed evidence connecting depression in T2DM and obesity. Some studies have shown that depression and depression symptoms are commonly seen in T2DM and obese patients. In contrast, there are studies where no such link has been found. However, there is a reported evidence showing a bidirectional relationship between depression and T2DM which could be explained basis neurobiological mechanism involved and may be attributed to dysregulation in the HPA axis with elevated cortisol levels, changes in corticotrophin-releasing hormone levels and neurotrophins.5,9

A recent meta-analysis by Gonzlez-Castro et al, assessed the risk of developing substantial depressive symptoms in individuals with obesity and T2DM and found the involvement of genetic, neurobiological and environmental factors that contribute considerably in the development of T2DM, obesity and depression, however, the risks of these conditions could be different between populations.5,10

On a closer look at the etiology of the disease triad, stress has been found as one of the well-established contributors responsible. There is a prudent possibility that patients with T2DM and obesity, depending on their stress responses, may or may not develop depression. The individuals response can form a Gaussian distribution of a population ranging from stress resilience to stress susceptible population, suggesting that some individual suffer greater neuropsychiatric pathophysiology than others.1114 The relatively minor stresses associated with diabetes have been thought to be enough to trigger depressive symptoms in vulnerable individuals. Both normal stressors and T2DM related distress have been linked with increased odds of developing depressive symptoms.14

In addition to stressful conditions, the body undergoes biochemical alterations to correct the imbalances and coordinates the stress response by releasing array of stress mediators in various temporal compartments of body, thus, offering a varied degree of susceptibility and resistance patterns. This mechanism has been studied by researchers, where some individuals show differential capability to cope/adapt with stress and form a distribution in a population ranging from high degree (resilient) to low degree of resistance (susceptible). The intriguing thing about stress is that, it does not affect individuals in a population, in a similar manner.1517

Further, extensive research has established that the most probable common biochemicals that link this disease triad are cortisol and adiponectin. However, the alterations in adipokines serum level that may be a possible link between depression and obesity, has not explored completely. Lower adiponectin levels and raised cortisol levels are seen in T2DM, obesity and depression cases individually, however, how these levels are affected in cases of comorbid conditions in entirety, and the information regarding modulation of adiponectin in diabetic and obese patients that will develop or not develop depression is unknown.1820

In the present study an attempt was made to understand the behavior of T2DM subjects who exhibit two distinctive behavioral phenotypes (one showing depressive behavior/symptoms and the other showing no depressive behavior or symptoms) associated with their differential sensitivity to stress (stress resilient or susceptible), quantified by stress questionnaire response and levels of biochemical markers directly or indirectly related to stress (adiponectin and cortisol).

The study rationale is presented in Figure 1.

Figure 1 The figure represents study rationale. The figure also depicts how biochemical parameters (cortisol and adiponectin) are associated with stress including both stress resilient and susceptible populations. ( mild increment; moderate increment; high increment; mild reduction; moderate reduction; high reduction; no change).

It is unknown whether any biochemical changes can be estimated in a population that can differentiate the population into stress-resilient and stress-susceptible individuals and further into those that will develop or not develop depression. The body coordinates the stress response by secreting multiple stress modulating mediators which includes transmitters (nor-epinephrine/epinephrine/serotonin), peptides (corticotrophin-releasing factor, dynorphins), hormones (cortisol in humans and corticosterone in rodents, angiotensin). The complexity of an orchestrated stress response occurs at various levels, but most theories revolve around cortisol levels. The imbalance in cortisol levels is a good predictor of the over-activated stress axis. The cross-play of cortisol is also found in metabolic disorders, particularly diabetes and obesity. Besides, adiponectins recent involvement, a collagen-like plasma protein secreted by adipocytes is also suggested to play a substantial role in the development of insulin resistance, obesity, and depression. The protein has been found to be decreased in cases of insulin resistance, diabetes, and depression, but what is the degree of reduction? The answer to this question is still unknown.

Therefore, in the present study, we aimed to identify the biochemical levels that can differentiate diabetic/obese peoplewith or without depression can undoubtedly help in the diagnosis and prognosis of these comorbid conditions. The most probable biochemical parameters that link all these three comorbid conditions of T2DM, obesity, and depression, are cortisol and adiponectin. The lower adiponectin levels are also reported with increased cortisol levels in diabetes, obesity, and depression individually. However, how these levels are affected in entirety and the information regarding modulation of adiponectin in diabetic and obese patients that will develop or not develop depression is unknown.

This was a cross-sectional study.

The investigation plan of the study is depicted in Figure 2.

Figure 2 The figure demonstrates investigation plan of the study.

Male and female patients, aged >18 years and <65 years, diagnosed with T2DM using the American Diabetes Association criterion of Hb1Ac 6.5% were enrolled after a written informed consent was obtained. Other inclusion criteria included, patients treated with antidiabetic treatment for at least last six months, body mass index 30.0 kg/m2, able to understand and comply with study procedures. Control group included male and female subjects aged >18 years and <65 years who provided written informed consent and had no clinically significant illness and/or disease such as absence of T2DM, no history or current depression/anxiety or any other psychiatric disorder, ability to understand and comply study procedures. Patients with a history or current smokers, drug or alcohol dependence, currently diagnosed or having history of any major psychiatric illness, uncontrolled hypertension (blood pressure 180/105 mmHg or above), patient on psychotropic drugs, pregnant or breast-feeding women, patients unable or unwilling to give written informed consent were excluded from the study. Patients visiting the diabetic clinic and medicine outpatient department (OPD) were approached for participation. Healthy controls visiting for routine check-ups or along with the patients were also approached for participation.

Demographic and clinical data were collected in the standard format for height, sex, age, weight, duration of T2DM and concomitant medications. The body mass index for each subject was deducted using standard formula. For T2DM patients, HbA1c and blood glucose levels were recorded and health check-up reports and biochemical parameters relevant to the study of the healthy participants were obtained.

The blood samples were collected in the early morning hours (between 06:00 and 08:00 am), where 5 mL approximate was obtained from participants in a fasting condition. The serum was separated from the blood according to the procedures mentioned in the ELISA manual. Serum adiponectin levels were quantified for each 40 L of serum samples using a highly sensitive ELISA kit (RayBio Human Acrp30 ELISA Kit).

As levels of cortisol in serum are affected by episodic secretion of cortisol and the resulting diurnal variation, samples were collected during early morning hours (between 06:00 and 08:00 am) to have consistent and uniform cortisol measurement. A blood sample of approximately 5 mL was obtained in a fasting condition. The serum was separated from the blood according to the standard procedures of ELISA and serum cortisol levels were quantified using chemiluminescence.

Stress Coping Resources Inventory questionnaire (SCQ) was used to assess the stress in patients. As people differ remarkably in their responses to potentially stressful events, about one in ten persons come out of captivity as mentally healthier. In contrast, others may face extreme emotional difficulty and find it difficult to cope with stress conditions. SCQ helps in the assessment of the factors that are associated with managing success. With high test-retest reliabilities and internal consistency, the SCQ helps anticipate personality type, emotional distress, occupational choice, life satisfaction, illness, and drug dependency.21

The state of depression/depressive symptoms was assessed using the well-accepted Patient Health Questionnaire (PHQ-9). PHQ-9 is a self-administered version of the diagnostic instrument for common mental disorders. It constitutes depression module, which scores nine DSM-IV domains. Each PHQ-9 domain is recorded using scores ranging from 03, depicting (not at all) or (nearly every day), respectively.22

Two clusters among the diabetic population were identified using the biochemical parameters (cortisol and adiponectin). The questionnaire-based scores (PHQ-9 and SCQ) and variables independently identified two other clusters among the T2DM population using K-means cluster analysis. After identification of clusters, ANOVA was performed on the control group (A) and diabetic group (B), and the two identified clusters from the diabetic group: diabetes/obese without depression (C1) and diabetes/obese with depression (C2). If p0.05 was detected in Tukeys test-based comparisons, the individual group results were considered significantly different. The clusters identified based only on biochemical parameters and those identified by the questionnaire-based scores (PHQ-9 and SCQ) were then compared to evaluate the accuracy of the identified clusters (meaning the same subjects were identified in two clusters from the diabetic groups C1 and C2). Cluster analysis was performed using R-project; R version 3.5.3.

The study was carried out to test the hypothesis that the subjects with T2DM demonstrates two phenotypes that can be identified based on (1) patients response to stress, estimated by questionnaire responses (PHQ-9 and SCQ), and; (2) the levels of biochemical markers directly or indirectly related to stress (adiponectin and cortisol). Assuming a typical SD of 40% (using a two-tailed t-test of difference between means) for adiponectin and cortisol levels, a sample size of 42 subjects per group (depression and no depression) and control (nondiseased) was considered sufficient to detect a significant difference of 20% between groups for cortisol and adiponectin levels (separately) with coverage probability of 95%, (=0.05, power=0.8, =0.2) giving a total population of 126 subjects. Considering a dropout rate of 20%, the sample size required was 153 (51 per group).23,24

The demographic characteristics are presented in Table 1. All study participants were administered PHQ-9 and SCQ questionnaires. Basis participants responses to PHQ-9, two clusters were identified (a) depressive and, (b) nondepressive phenotype. SCQ scores were then used to identify two independent clusters, (a) stress susceptible and, (b) stress-resilient. The literature evidence also suggests the indirect possibilities of two phenotypes (a) diabetic/obese with depression and (b) diabetic/obese without depression. The strength of these questionnaires in identifying the same clusters from the diabetic population in the study alludes to the possibility of differential responses to stress and further risk(s) of developing depression. Central to the hypothesis of these identified clusters different from each other and yet similar in HbA1c and BMI values indicates the homogeneity of diabetes population in the background, but when looking closely at the level of stress responses sheds light on the two phenotypes (Tables 2 and 3). As a result, shown in Figure 3A, 83% similarity of clusters (C1 and C2) and no clusters identified in control population further strengthens that there is one subset of the diabetic population which is at higher propensity to develop depression (stress vulnerable) compared to another subset which is resilient to the effects of stress.

Table 1 Demographic Characteristics

Table 2 Independent Cluster Analysis Based on Scores from PHQ-9 and SCQ Questionnaires

Table 3 K-means Cluster Analysis: Identify Two Clusters Based on Scores from PHQ-9 and SCQ Questionnaires

Figure 3 The figure demonstrates cluster similarity across study population of diabetes. (C1: diabetic/obese patients without depression; C2: diabetic/obese patients with depression). (A) Similarity of clusters based on questionnaire scores: two clusters were identified by independently using SCQ and PHQ-9 questionnaire score as variables employing K-means cluster analysis. The independent clusters (C1 and C2) identified by SCQ scores and (C1 and C2) of PHQ-9 scores were matched subject to subject for accuracy estimations. (B) Similarity of clusters based on biochemical evaluations: two clusters were identified by independently using adiponectin and cortisol levels as variables employing K-means cluster analysis. The independent clusters (C1 and C2) identified by adiponectin levels and (C1 and C2) of cortisol levels were matched subject to subject for accuracy estimations. (C) Similarity of clusters based on questionnaire scores vs biochemical evaluations: two clusters were identified by independently using (1) SCQ and PHQ-9 questionnaire score as two variables together and (2) adiponectin and cortisol levels as two variables together. The independent clusters (C1 and C2) identified by questionnaire scores and of (C1 and C2) of biochemical evaluations were matched subject to subject for accuracy estimations.

Similar clusters from the diabetic population were identified based on biochemical estimations of adiponectin and cortisol (Tables 4 and 5). First, individual cluster analysis was conducted where subjects were categorized into clusters based on cortisol (p-value <0.001) and adiponectin levels (p-value=0.001) followed by combined cluster analysis using both biochemical parameters (Table 5). Cluster similarity was found in 71% of subjects (Figure 3A and B).

Table 4 Independent Cluster Analysis Based on Cortisol and Adiponectin Levels

Table 5 K-means Cluster Analysis: Identify Two Clusters Based on Cortisol and Adiponectin Levels

Further, the cluster symmetry/similarity was assessed based on biochemical parameter analysis and was compared with questionnaire responses where, the accuracy of similar cluster formation by these two independent analyses was found as 85% (Figure 3C). Considering the same clusters (C1 and C2) identified, final clustersdiabetic obese without depression (diabetic/obese-C1) and diabetic obese with depression (diabetic/obese-C2)were identified utilizing questionnaire response and biochemical parameter estimations together. Of 105 diabetic subjects, 61 (58%) belong to C1 and 44 (42%) to the C2 group.

The next question addressed in the study was how much these identified clusters in a diabetic population are (1) different from each other; (2) different from parent diabetic pool (2) and different from the control population in the study. The diabetic population group was different from control. When these clusters were tested for the percentage change in comparison to the control population and their parent diabetic population, for BMI, HbA1C, the clusters and parent diabetic pool were similar to each other; however, both the clusters and diabetic pool have significantly higher BMI, HbA1C values compared to control (Figure 4; Table 6). BMI values of diabetic parent pool (27%), diabetic/obese: C1 (26%), and diabetic/obese: C2 (27%) were significantly higher in comparison to control and (2) HbA1c values of diabetic parent pool (87%), diabetic/obese: C1 (87%), and diabetic/obese: C2 (87%) significantly higher in comparison to control. The similarity of BMI values and HbA1c values of the diabetic pool and the two clusters reinforces the homogeneity of the diabetic population across the standard markers of a diabetes diagnosis.

Figure 4 Percent change from control of total diabetes populations and two identified clusters among diabetes population (C1: diabetic/obese patients without depression; C2: diabetic/obese patients with depression).

Table 6 Variations of Different Variables

When these clusters were tested for percentage compared to control the population and their parent diabetic population, for cortisol and adiponectin levels, the clusters were different from each other and from the parent diabetic pool (Figure 4; Tables 6 and 7). Serum level of cortisol in the diabetic parent pool (7%) showed no change, diabetic/obese: C1 (20%) showed significantly lower, and diabetes: C2 (45%) showed significantly higher values in comparison to control and serum level of adiponectin of diabetes parent pool (61%), diabetic/obese-C1 (56%), and diabetic/obese: C2 (71%), all showed significantly lower values in comparison to control. A point to note for both clusters, and these changes were statistically different irrespective of the direction of change. Though serum cortisol levels of the diabetic pool were not different from the control population, in identified clusters, the marked differentiation of diabetic/obese: C1 showed lower values of cortisol and diabetic/obese: C2, showing higher values of cortisol, suggesting that diabetic/obese: C1 can be considered stress-resilient. The group diabetic/obese: C2 can be regarded as stress vulnerable owing to high values of cortisol linked to a higher degree of stress perception. The argument is further strengthened with adiponectin levels showing a lower reduction in diabetic/obese: C1 (56%) compared to diabetic/obese: C2 (71%) with an absolute 15% more reduction in diabetic/obese: C2 (stress vulnerable based on cortisol values) goes well with the literature wherein lower values of adiponectin are associated with stress perception. A point to note is that diabetes, being the background disease, is shown to have lower adiponectin values than control, which aligns with the available literature. The diabetic pools clusters reinforce that the stress vulnerable (diabetic/obese: C2) based on cortisol values have much lower adiponectin values than the stress-resilient group (diabetic/obese: C1).

Table 7 ANOVA Variance Analysis Results for Different Variables

When these clusters were tested for percent change compared to the control population and their parent diabetic population, for PHQ-9 and SCQ scores, the clusters were different from each other and the parent diabetic pool (Figure 4; Tables 6 and 7). PHQ-9 scores of the diabetic parent pool (50%) showed significantly higher, diabetic/obese: C1 (3%) showed no change, and diabetic/obese: C2 (123%) showed significantly higher values in comparison to control and SCQ scores of the diabetic parent pool (4%) showed no change, diabetic/obese: C1 (15%) showed significantly higher, and diabetic/obese: C2 (33%) showed significantly lower values in comparison to control. A point to note for both clusters, is that the changes were statistically different irrespective of the direction of change. Though SCQ scores of the diabetic pool were not different from the control population, however, in identified clusters, the marked differentiation of diabetic/obese: C1 showing higher scores (representative of stress coping capacity) and diabetic/obese: C2 showing lower scores (suggestive of stress no-copers). This further highlights that diabetic/obese: C1 is a stress-resilient population which is in line with the observed cortisol (lower values than C2) and adiponectin response (higher values than C2) in this study. The differentiation of cluster is further strengthened with PHQ-9 scores showing the propensity of stress vulnerable population (diabetic/obese: C2) of the absolute average score of 13.4 (123% higher score than control) and stress-resilient population (diabetic/obese: C1) of the absolute average score of 5.8 (no change from control). The data further suggests that the diabetic population has a significantly higher PHQ-9 score (9.0; 50% higher score than control), which apparently is coming from the diabetes/obese-C2 cluster. The higher scores of diabetic/obese: C2 cluster are suggestive of moderately depressed phenotype, which goes well with complete data wherein this group has high cortisol values, comparatively lower adiponectin values, lower SCQ scores, and high PHQ-9 scores and diabetic/obese: C1 cluster with no markers (biochemical or questionnaire-based) indicating depression conferring to their strong stress-resilient mechanisms.

Reduced levels of adiponectin in T2DM patients were seen in comparison to control group, which supports the fact that higher adiponectin levels are associated with a lower risk of T2DM. Adiponectin is one of the consistent biochemical predictors of T2DM which is under investigation worldwide. However, the studies have not yet established the scientific basis of the causality, the consistency of this association across large and diverse populations, any possible dose-response relationship, and the supportive findings in studies that may indicate that adiponectin might be a promising target for the reduction of risk of T2DM.15 A similar cross-sectional study demonstrated significantly lower adiponectin levels in diabetics than in nondiabetic participants.25 Similar findings were seen in a community-based research and a prospective longitudinal study with a follow-up of three years.26,27 Adiponectin has been suggested to activate the AMP-activated protein kinase pathway, resulting in reduced serum level of glucose. It also has anti-inflammatory and insulin-sensitizing properties. Insulin resistance and obesity have been linked to metabolic inflammation believed to trigger T2DM development.28

Multiple cross-sectional clinical studies have demonstrated high depression prevalence in T2DM patients.26,29 In similarity, the present study also observed that T2DM obese patients with depression had a lower adiponectin levels compared to T2DM obese patients without depression. Various meta-analyses and clinical studies have indicated that depressive patients have a decreased adiponectin level compared to healthy subjects.3032 These findings are supported by preclinical evidence. In an animal study, activation of depressive-like behavior induced by stress was seen when neutralizing antibodies of adiponectin were injected. The depressive behavior was reversed once the exogenous adiponectin was injected in diabetic mice and it resulted in antidepressant-like behavioral changes.33

The present study also showed increased serum cortisol levels in T2DM obese patients with comorbid depression compared to the group without depression, which is in concurrence with the reported findings.3436 Dysregulation in the hypothalamic-pituitary-adrenal (HPA) axis and release of cortisol plays a pivotal role in depression pathophysiology.37 Hypothalamus further secretes arginine, vasopressin, and corticotropin-releasing hormone in response to various stressors, both psychological and physical.38

It is extensively suggested that raised secretion of cortisol during chronic stress leads to depression.39

Metabolic disorder is linked with the fluctuating plasma level of cortisol, a key player that triggers a higher risk of insulin resistance, hyperglycemic state, upsurge in hypertension cases, reduced high-density lipoprotein cholesterol (HDL-C), elevated triglycerides, and abdominal obesity.40 T2DM also triggers differential cortisol levels during stress and depression, further increasing the risk of metabolic syndrome. It was also reported that adiponectin is involved in various physiological events including regulating deposition of visceral fats, triglyceride levels and acts as an anti-atherosclerotic and anti-inflammatory.41 Presence of T2DM also alters the plasma level of adiponectin and affects associated functions that might increase the likelihood of developing metabolic disorders. Stress and depression also have a distinct impact on adiponectins plasma level which triggers the risk of metabolic disease via a parallel mechanism.

The cross-sectional design of this study did not allow (1) longitudinal follow-up to assess the changes in adiponectin and cortisol along with glycemic control over a period of time. (2) The interference of concurrent medications on the questionnaire responses and biochemical levels cannot be ruled out. (3) Clinical studies involving the use of antidiabetics and antidepressants that may have effects on the other disease symptoms can add benefit to validate the data produced.

Evidence suggests that depression is present in about one-third of T2DM patients.42

Our study demonstrates that presence of depression increases from one-third to one-half in T2DM patients, if patient have additional comorbidity of obesity. Glycemic control in T2DM patients having obesity and depression is difficult to maintain by reaching their HbA1c goals. Factors including patient adherence to medication as a lever of good self-care practices is limited in depressive conditions, and they have twofold risk of missing doses compared with those without depression. Frequent monitoring of glycaemic control is considerably more important to T2DM/obese patients exhibiting clinical signs of depression.

The results accumulated in the study may not reflect the true burden of depression in T2DM/obese pool. The patients were screened and selected from a specialized tertiary hospital in a metropolitan area of Delhi. Doing dynamic real-world evidence studies in primary/secondary health care setting will be reflective of true the burden of depressive phenotype in the T2DM/obese pool. Our study did not include non-T2DM/obese controls having depression for comparison, limiting the inferences linking the triad of diabetes, obesity, depression and possible role of diabetes/obesity in depression and reciprocated effects on durability of glycemic control. Cross-sectional study by design only allowed to bring the associations between diabetes/obesity and depression, however, a longitudinal study design will be best suited to investigate the interdependencies of comorbidities.

The study protocol and informed consent were approved by the Jamia Hamdard Institutional Ethics Committee.

The authors would like to thank Jamia Hamdard University, New Delhi and Hamdard Institute of Medical Sciences and Research, HAH Centenary Hospital for facilitating study conduct. The authors convey gratitude to various departments/centers for research support in this study.

The study was not sponsored by any grant.

The authors report no conflicts of interest in this work.

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[Full text] Evaluation of Stress and Associated Biochemical Changes in Patients wi | DMSO - Dove Medical Press

NEW YORK, Feb. 18, 2021 /PRNewswire/ --Immunic, Inc. (Nasdaq: IMUX),a clinical-stage biopharmaceutical company developing a pipeline of selective oral immunology therapies aimed at treating chronic inflammatory and autoimmune diseases, today announced positive top-line data from an investigator-sponsored phase 2 proof-of-concept clinical trial of IMU-838 in primary sclerosing cholangitis (PSC). This single-arm, open-label, exploratory study was designed to investigate IMU-838's potential to improve various biochemical parameters in PSC patients and help determine whether any such activity warrants further investigation in randomized PSC trials. As previously announced, due to the COVID-19 pandemic, only 18 of the targeted 30 patients were enrolled in the study (intent-to-treat population, ITT), of whom only 11 patients completed the full IMU-838 treatment course and were evaluable over the 24-week treatment period (per-protocol population, PP).

The PP population experienced a statistically significant decrease in serum alkaline phosphatase (ALP) levels (p=0.041) after 24 weeks of treatment using 30 mg IMU-838 once daily, as compared to baseline. A consistent individual pattern of a stable decrease in ALP values was observed in the PP population between baseline and week 24, without any single patient showing an increase of more than 20% of ALP. As per the definition of the primary objective of the study, 27.3% of the patients in the PP population had a clinically relevant reduction of serum ALP higher than 25% at week 24, without an increase in liver biochemistry of more than 33%, as compared to baseline. Biochemical endpoints, such as changes in serum ALP, have been used in PSC trials performed by third parties.

Regarding the secondary objectives of the study, no changes in aspartate aminotransferase (AST), alanine aminotransferase (ALT), or total, direct or indirect bilirubin were observed in the ITT or PP populations, as compared to baseline. In addition, despite the limited scope of the data, encouraging results were observed regarding symptoms of inflammatory bowel disease, a common comorbidity for PSC patients, and patient assessments of health-related quality of life. The study also found that IMU-838 is a safe and well-tolerated oral drug for PSC patients and treatment-emergent adverse events were rare and generally mild.

"I am very excited about the effects we have seen in this highly underserved patient population where there is only a small number of cases worldwide and where no pharmaceutical treatment option is currently available," noted Daniel Vitt, Ph.D., Chief Executive Officer and President of Immunic. "We are also very pleased to see that IMU-838's safety and tolerability profile was confirmed in this patient group. The results from this small, open-label study suggest that IMU-838 merits further clinical testing in PSC. We are in discussions with investigators and leading clinical experts to further evaluate the data set and to explore potential next steps for this indication."

"Currently, no effective treatment options are available for PSC patients and the hepatology community is very keen to see new approaches and clinical programs for the investigation of promising new approaches. I am grateful that Mayo Clinic and Immunic are collaboratively exploring this underserved indication for which liver transplantation is often the only effective option," stated Keith Lindor, M.D., Professor of Medicine Emeritus and former President of the American Association for the Study of Liver Diseases. "Although we are mindful of the small size of this dataset, I do believe the results are noteworthy and merit further exploration. Notable in this small patient cohort is the absolute consistency with which these patients experienced decreases in serum alkaline phosphatase at the 24-week time point."

Study Background and Baseline Characteristics

The single-arm, open label, exploratory study was an investigator-sponsored trial led by Elizabeth Carey, M.D., Professor of Medicine, Division of Gastroenterology and Hepatology, Department of Internal Medicine, Mayo Clinic, who had received Investigator Investigational New Drug (IND) approval from the U.S. Food & Drug Administration (FDA) and had been granted Institutional Review Board (IRB) approval to conduct the study. The study was supported by a grant from the National Institutes of Health (NIH) and was conducted at two sites: Mayo Clinic, Phoenix, Arizona (Dr. Carey) and Mayo Clinic, Rochester, Minnesota (John E. Eaton, M.D.), both of which are tertiary referral centers for PSC patients.

The study, for which Immunic provided the study medication, planned to enroll 30 patients with PSC, aged 18 to 75 years, who received 30 mg of IMU-838 once daily for a period of 24 weeks. Enrollment for the study took place between July 2019 and September 2020, but almost all enrollment occurred in 2019 and early 2020. During the COVID-19 pandemic, recruitment for this study was hampered, as patients with PSC are at a high risk of COVID-19 infections and were advised to avoid travel and unnecessary social contacts such as those required to participate in a clinical trial. Together with the investigators, Immunic determined to readout data of the 18 patients who were enrolled prior to the COVID-19 pandemic. The ongoing COVID-19 pandemic also triggered the principal investigator's decision to terminate the study in late 2020, before the intended recruitment goal of 30 patients was reached.

A total of 18 patients started treatment of 30 mg IMU-838 once daily (intent-to-treat population, ITT, n=18). Of these 18 patients, 11 patients received the full 24-week treatment with IMU-838 (per-protocol population, PP, n=11). Due to the high number of discontinued patients during the COVID-19 pandemic and the fact that all discontinued patients in an ITT statistical analysis will be counted as treatment failures at week 24, this analysis focuses mainly on the 11-patient PP population.

Primary Objective

The primary objective of this study was to determine whether IMU-838 reduces serum ALP in adult patients diagnosed with PSC. The main analysis for the primary objective was whether patients could achieve a reduction of ALP at week 24 which is greater or equal to 25%, as compared to baseline, while the AST increase at week 24 is no more than 33%, as compared to baseline. This positive primary outcome was achieved by 3 of 11 patients in the PP population (27.3%, 95% CI: 6-61%). By virtue of inclusion criteria, patients at baseline had to have an elevated ALP value of at least 1.5 times upper limit of normal (ULN).

In addition, time from baseline was calculated as a continuous variable and treated as the primary predictor using a random intercept model which was adjusted for age at baseline and gender. For this longitudinal analysis of ALP from baseline to week 24 in the PP population, the ALP value statistically significantly (p=0.041) decreased by an average of 5.76 IU/L every 30 days (95% CI: -11.29, -0.23; statistical model). The time trend was not statistically significant in the ITT analysis (p=0.578) due to missing data following the high rate of treatment discontinuations during the COVID-19 pandemic.

Secondary Objectives

Secondary objectives were to investigate the liver biochemistry parameters, AST, ALT, and total/direct/indirect bilirubin, as well as the concentrations of proinflammatory cytokines, as compared to baseline. The longitudinal analysis of both AST and ALT as well as total, direct and indirect bilirubin values showed a stable pattern in the PP population with no statistically significant change over time and the confidence interval to include the no-change scenario (AST: average 30 day change 1.22 IU/L, 95% CI: -0.53, 2.97, p=0.170; ALT: average 30 day change 0.85 IU/L, 95% CI -1.46, 3.15, p=0.467, total bilirubin: average 30 day change 0.00 mg/dL, 95% CI -0.01, 0.02, p=0.561, direct bilirubin: average 30 day change 0.00 mg/dL, 95% CI -0.01, 0.01, p=0.861, indirect bilirubin: average 30 day change 0.00 mg/dL, 95% CI -0.01, 0.01, p=0.556). Similar results were found in the ITT population. In addition, a decrease in the Ulcerative Colitis Clinical score was observed in evaluated patients, although the number of assessed patients was limited.

"This was a feasibility study to explore activity of IMU-838 in PSC patients based on biochemical parameters. IMU-838 was found to lead to a statistically significant reduction of serum ALP over time in the PP population, while no trend for increases in ALT, AST or bilirubin was observed," commented Andreas Muehler, M.D., Chief Medical Officer of Immunic. "Despite the challenges we faced due to COVID-19, which severely hindered the enrollment at the two Mayo Clinic sites and which led to an unusually high discontinuation rate and an early termination of the study, we have seen encouraging activity signals for IMU-838 in this patient population. Based on these promising data and, in particular, the improvement in biochemical liver parameters, we will continue to evaluate the potential of IMU-838 as a treatment option for PSC patients. It may also be worthwhile to optimize dose levels of IMU-838 in PSC patients in the future."

For more information on this clinical trial, please visit: http://www.clinicaltrials.gov, NCT03722576.

Conference Call and Webcast Information

As previously announced, Immunic's management team will host a public conference call and webcast today, February 18, 2021 at8:00 a.m. Eastern Timeto discuss the data from the main phase 2 analysis of the CALVID-1 trial of IMU-838 in hospitalized patients with moderate COVID-19, as well as data from the investigator-sponsored phase 2 clinical trial of IMU-838 in primary sclerosing cholangitis.

To participate in the conference call, dial 1-877-870-4263 (USA) or 1-412-317-0790 (International) and ask to be joined into the Immunic, Inc. call. A live, listen-only webcast of the conference call can be accessed at https://www.webcaster4.com/Webcast/Page/2301/39950or on the "Events and Presentations" section of Immunic's website at ir.imux.com/events-and-presentations.

An archived replay of conference call and webcast will be available approximately one hour after the completion for one year on Immunic's website at: ir.imux.com.

About Primary Sclerosing Cholangitis (PSC) PSC is a rare liver disease with a prevalence of approximately 4.15 per 100,000 in the United States, in which the bile ducts in the liver become inflamed, narrow and prevent bile from flowing properly. The exact cause and disease mechanism of PSC are still unknown, but an autoimmune mechanism may play a role. There is an association with inflammatory bowel diseases, most often with ulcerative colitis and less commonly with Crohn's disease. PSC is a progressive disease and, other than liver transplantation, there are currently no approved therapies that have been shown to improve survival in patients with PSC. The estimated time from diagnosis of PSC to death or liver transplant has been shown to be less than 15 years.

About IMU-838IMU-838 is an orally available, next-generation selective immune modulator that inhibits the intracellular metabolism of activated immune cells by blocking the enzyme dihydroorotate dehydrogenase (DHODH). IMU-838 acts on activated T and B cells while leaving other immune cells largely unaffected and allows the immune system to stay functioning, e.g. in fighting infections. In previous trials, IMU-838 did not show an increased rate of infections compared to placebo. In addition, DHODH inhibitors, such as IMU-838, are known to possess a host-based antiviral effect, which is independent with respect to specific virus proteins and their structure. Therefore, DHODH inhibition may be broadly applicable against multiple viruses. IMU-838 was successfully tested in two phase 1 clinical trials in 2017 and is currently being tested in a phase 2 trial in patients with ulcerative colitis. In the third quarter of 2020, the company reported positive results from its phase 2 EMPhASIS trial of IMU-838 in relapsing-remitting multiple sclerosis, achieving both primary and key secondary endpoints with high statistical significance. In the first quarter of 2021, Immunic announced that IMU-838 has shown evidence of clinical activity in its phase 2 CALVID-1 trial in hospitalized patients with moderate COVID-19. Also, in the first quarter of 2021, the company reported positive top-line data from an investigator-sponsored phase 2 proof-of-concept clinical trial of IMU-838 in primary sclerosing cholangitis which was conducted in collaboration with Mayo Clinic. To date, IMU-838 has been tested in more than 800 individuals and has shown an attractive pharmacokinetic, safety and tolerability profile. IMU-838 is not yet licensed or approved in any country.

About Immunic, Inc.Immunic, Inc. (Nasdaq: IMUX) is a clinical-stage biopharmaceutical company witha pipeline of selective oral immunology therapies aimed at treating chronic inflammatory and autoimmune diseases, including relapsing-remitting multiple sclerosis, ulcerative colitis, Crohn's disease, and psoriasis. Immunic is developing three small molecule products: its lead development program,IMU-838, is a selective immune modulator that inhibits the intracellular metabolism of activated immune cells by blocking the enzyme DHODH and exhibits a host-based antiviral effect; IMU-935 is an inverse agonist of RORt; and IMU-856 targets the restoration of the intestinal barrier function. For further information, please visit: http://www.imux.com.

Cautionary Statement Regarding Forward-Looking StatementsThis press release contains "forward-looking statements" that involve substantial risks and uncertainties for purposes of the safe harbor provided by the Private Securities Litigation Reform Act of 1995. All statements, other than statements of historical facts, included in this press release regarding strategy, future operations, future financial position, future revenue, projected expenses, prospects, plans and objectives of management are forward-looking statements. Examples of such statements include, but are not limited to, statements relating to Immunic's three development programs and the targeted diseases; the potential for IMU-838 to safely and effectively target diseases; the proof-of-concept study of IMU-838 for the treatment of patients with primary sclerosing cholangitis; the timing of current and future clinical trials; the potential for IMU-838 as a treatment for primary sclerosing cholangitis that may be supported by the investigator-sponsored phase 2 proof-of-concept trial data, and any clinical trials, collaborations and approvals relating to such potential treatment; the nature, strategyand focus of the company; and the development and commercial potential of any product candidates of the company. Immunic may not actually achieve the plans, carry out the intentions or meet the expectations or projections disclosed in the forward-looking statements and you should not place undue reliance on these forward-looking statements. Such statements are based on management's current expectations and involve risks and uncertainties. Actual results and performance could differ materially from those projected in the forward-looking statements as a result of many factors, including, without limitation, the COVID-19 pandemic, risks and uncertainties associated with the ability to project future cash utilization and reserves needed for contingent future liabilities and business operations, the availability of sufficient resources to meet business objectives and operational requirements, the fact that the results of earlier studies and trials may not be predictive of future clinical trial results, the protection and market exclusivity provided by Immunic's intellectual property, risks related to the drug development and the regulatory approval process and the impact of competitive products and technological changes. A further list and descriptions of these risks, uncertainties and other factors can be found in the section captioned "Risk Factors," in the company's Annual Report on Form 10-K for the fiscal year ended December 31, 2019, filed with the SEC on March 16, 2020, the company's Quarterly Report on Form 10-Q for the quarter ended September 30, 2020, filed with the SEC on November 6, 2020, and in the company's subsequent filings with the Securities and Exchange Commission. Copies of these filings are available online at http://www.sec.gov or ir.imux.com/sec-filings. Any forward-looking statement made in this release speaks only as of the date of this release. Immunic disclaims any intent or obligation to update these forward-looking statements to reflect events or circumstances that exist after the date on which they were made. Immunic expressly disclaims all liability in respect to actions taken or not taken based on any or all the contents of this press release.

Contact Information

Immunic, Inc. Jessica BreuHead of Investor Relations and Communications+49 89 2080 477 09[emailprotected]

US IR ContactRx Communications GroupPaula Schwartz+1 917 322 2216[emailprotected]

US Media ContactKOGS CommunicationEdna Kaplan+1 781 639 1910[emailprotected]

SOURCE Immunic, Inc.

http://www.immunic-therapeutics.com

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Immunic, Inc. Announces Positive Top-Line Data From Investigator-Sponsored Phase 2 Proof-of-Concept Clinical Trial of IMU-838 in Primary Sclerosing...

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