**ADVANCES IN BIOENGINEERING**

Edited by **Pier Andrea Serra**

#### **Advances in Bioengineering**

http://dx.doi.org/10.5772/58642 Edited by Pier Andrea Serra

#### **Contributors**

Rodica-Mariana Ion, Rino Morent, Gaelle Aziz, Nathalie De Geyter, Toru Yazawa, Michelle Yongmei Wang, Chris Zwilling, Shlomo Margel, Michal Kolitz-Domb, Pieter Cools, Farzad Asgarian, Mohsen Judy, Alireza Akhavian, Gaofeng Zhou, Ifana Mahbub, Syed Kamrul Islam, Farhan Quaiyum, Md Sakib Hasan, Mauro C. Moreira, Eduardo Bauer, Yasmim Guterres, Alexandre Campos, Yu Nagase, Yosuke Okamura, Mario Letelier, Jaroslav Turánek, Zuzana Kauerova, Robert Lukáč, Josef Mašek, Štěpán Koudelka, Andrew Miller, Milan Raška

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**6. Conclusion**

The challenge here is to reshape the higher education environment and to develop struc‐ tures that enable both educators and students to flourish in educatively supportive cultures. Huyton [94] argues that failure to recognize the importance of emotional labour can have a detrimental effect on educators and the pastoral support service they provide to students. We argue that recognition of care for academics themselves and not just their capacity to provide emotional support for others is essential. While some argue that workload allocations must include 'emotion work' [45], it is difficult to see in the current climate of performativity how this could actually gain traction. However, turning a blind eye to it is not the answer either. Higher education institutions need to become more supportive, empowering and healthy places where both students and staff can develop personally, socially and intellectually. Given the once traditional academic freedom of the academic (albeit clearly currently under siege), who if not academics will stand as the final bulwark against the insidious and perva‐ sive problem of neo‐liberalism and new managerialism in education and in particular the clearly stressful and adverse consequences it is having on the educational experience of all.


2.1.3. PPARs Agonist: Bezafibrate

Bezafibrate is a pan-peroxisome proliferator-activated receptor (PPAR) agonist and, in combination with UDCA, was demonstrated to have a potent activity in PBC due to its specific anticholestatic properties. PPARs are nuclear receptors regulating the transcription of genes involved in metabolic pathways and inflammation. They exist in three isotypes (PPAR-α, PPAR-γ, and PPAR-β/δ), with different tissue distributions and actions. PPARα are mainly expressed in hepatocytes, where they stimulate multidrug resistance protein 3 (MDR3) expression, which protects cholangiocytes against bile salt due to its effect on phosphatidylcholine secretion [21]. Moreover, PPARα has an anti-inflammatory action that is based on trans-repression of AP1 and NF-kB signaling, transcription factors responsible for the expression of many genes involved in inflammation, oncogenesis, and apoptosis [2]. PPARβ/δ, specifically expressed in hepatocytes, cholangiocytes, Kupffer cells, and hepatic stellate cells, plays a role in the progression of PBC due to its anti-inflammatory effects. PPARδ is also involved in the transport and the absorption of bile components [22]. PPARγ, expressed in Kupffer cells, has anti-inflammatory activity, and its agonist is proved to reduce portal inflammation in murine models of PBC [23]. Bezafibrate was evaluated in the BEZURSO trial, a two-month, double-blind, randomized, placebo-controlled phase 3 trial, in which the combination of UDCA and bezafibrate 400 mg was compared with UDCA and placebo in 100 patients who had an inadequate response to UDCA according to the Paris 2 criteria. The primary endpoint of the study was a complete biochemical normalization at 24 months. Interesting, the primary endpoint was achieved by 37% of patients treated with bezafibrate and 0% of patients in the control group. Moreover, 67% of the patients treated with bezafibrate reported a normalization of ALP, compared to 2% in the placebo group. Itch improved in almost one-third of patients. Histologic data were too limited to determine whether bezafibrate had a role in the reduction of liver fibrosis and hepatic inflammation; however, a significant decrease in liver stiffness and Enhanced Liver Fibrosis score was observed. With the exception of the well-known side effects of fibrates (myalgias and increases in creatinine and transaminases), no statistical differences regarding adverse events between the two groups were observed. As a precaution, bezafibrate should be administered with caution in patients at risk for chronic kidney disease (e.g., diabetes, hypertension, or established renal disease) [24]. Moreover, another study on PBC patients with a suboptimal response to UDCA proved that a long-term treatment with UDCA and bezafibrate has an excellent effect on pruritus. As a matter of fact, after a median of

38 months, all but one patient reported a partial or complete itching relief, and a recurrence or worsening of pruritus was observed after bezafibrate discontinuation [25].

Fenofibrate is another PPARα-agonist, and it was also studied in PBC patients. A retrospective study on patients treated with UDCA and fenofibrate, compared with patients treated only with UDCA, proved that the fenofibrate-treated group had a significant improvement in the biochemical parameters, in particular ALP and ALT [26]. The same effect on ALP was demonstrated in another retrospective study on PBC patients with a suboptimal response to UDCA treated with fenofibrate and UDCA [27], but more studies and randomized controlled trials are needed to understand its role in PBC.

#### 2.1.4. Corticosteroid: Budesonide

Budesonide is a potent synthetic corticosteroid with a high first-pass metabolism within the liver, resulting in few systemic side effects compared to other systemic steroids. It is an agonist of the nuclear glucocorticoid receptor (GR) and pregnane X receptor (PXR). Budesonide and UDCA have a synergic activity in increasing the expression of the biliary chloride/bicarbonate anion exchanger 2 (AE2) with the result of an increase in biliary secretion of bicarbonate and stabilization of the biliary bicarbonate umbrella [3]. Previous studies showed that budesonide improves liver histology and biochemistry in PBC patients with interface hepatitis on biopsy [28,29]. In contrast, in a recent three-year phase-III, double-blind, randomized trial comparing budesonide vs. placebo, patients treated with UDCA showed that budesonide combined with UDCA was not associated with an improvement in liver histology in patients with PBC and an inadequate response to UDCA. It is important to mention that the study was underpowered for the evaluation of the liver histology due to challenges in patient recruitment. Improvements in biochemical markers of disease activity were demonstrated in secondary analyses [30]. Budesonide should be avoided in cirrhotic patients because of the increased risk of portal vein thrombosis and uncontrolled systemic shunting of the drug [31].

#### *2.2. Therapies Evaluated in Clinical Trials*

The main aspects of the clinical trials are described in Table 1.

**Table 1.** Principal characteristics of the study of the drugs in clinical trials.

**Table 1.** *Cont.*

\* estimated.

#### 2.2.1. Non-Bile Acids FXR Agonists

Many FXR non-steroid agonists were investigated in PBC.

Cilofexor, a synthetic nonsteroidal FXR ligand, is involved in the transcriptional regulation of genes that play a role in bile acid metabolism. Cilofexor was tested in a phase 2 placebo-controlled, 12-week study on PBC patients. Cilofexor 100 led to a decrease in ALP (median reduction −13.8%; *p* = 0.005 vs. placebo), in GGT (−47.7%; *p* < 0.001), in ALT (−17.8%, *p* = 0.08), and in C-reactive protein (CRP; −33.6%, *p* = 0.03). Unfortunately, grade 2–3 pruritus occurred in 39% of the patients treated with Cilofexor 100 mg, compared with 10% in Cilofexor 30 mg and in 8% of patients treated with placebo. Pruritus led also to treatment discontinuation in 7% of patients on Cilofexor 100 mg [32].

Tropifexor (LJN452) is a non-bile acid FXR agonist investigated in a double-blind, randomized, placebo-controlled, phase 2 study ("A Multi-part, Double Blind Study to Assess Safety, Tolerability and Efficacy of Tropifexor (LJN452) in PBC Patients", NCT02516605) that evaluated the safety and the efficacy of different doses of Tropifexor (30 μg, 60 μg, and 90 μg) in patients with an inadequate response to UDCA [33]. As opposed to OCA, Tropifexor should not have major effects on the lipid profile, being a non-steroidal molecule. To elude the confounding effect of ALP gene induction mediated by FXR, the endpoint of this trial was set on the reduction in GGT levels. After four weeks, interim analysis showed a dose-dependent reduction in GGT, ALP, and hepatocellular damage (ALT). Therefore, this study indicates the potential benefit of Tropifexor in PBC, and further studies are warranted [45].

EDP-305 is another FXR agonist that was evaluated in PBC because of its antifibrotic effect in animal models [46]. A phase 2 double-blind, placebo-controlled trial assessing the safety, pharmacokinetics, and efficacy in patients with PBC and inadequate response or intolerance to UDCA was just completed ("A Study to Assess the Safety, Tolerability, Pharmacokinetics and Efficacy of EDP-305 in Subjects With Primary Biliary Cholangitis", NCT03394924). In the intent-to-treat analysis recently announced, EDP-305 did not meet the primary endpoint as defined by at least a 20% reduction in ALP, but key secondary endpoints (changes in ALT, AST, and GGT compared with placebo) at week 12 were reached in both the EDP-305 1 mg arm and the 2.5 mg arm.

#### 2.2.2. PPAR Agonists

Seladelpar is a new selective agonist of the PPARδ receptor, which has an antiinflammatory and choleretic activity. The first phase 2 clinical trial that investigated the effect in PBC patients nonresponsive to UDCA was prematurely terminated because of the occurrence of a reversible grade 3 increase in transaminase levels in three patients [34]. A new phase 2 study evaluating a lower dose of Seladelpar (5 mg and 10 mg) was recently performed. The 12-week interim results, first published at the AASLD Liver Meeting in 2017, showed a drop in ALP in 45% and 82% of patients in the 5 mg group and 10 mg group, respectively, and a normalization of ALP in 12% of the 5 mg group and 45% of the 10 mg group, respectively [35]. Given the promising results of the interim analysis, another clinical trial evaluating the efficacy and the safety of Seladelpar 2 mg, 5 mg, and 10 mg is ongoing (NCT02955602). Finally, at the end of 2018, the ENHANCE trial started. It was a 52-week, double-blind, placebo-controlled, randomized phase 3 study that included subjects with PBC and an inadequate response to UDCA or intolerance to UDCA ("ENHANCE: Seladelpar in Subjects With Primary Biliary Cholangitis (PBC) and an Inadequate Response to or an Intolerance to Ursodeoxycholic Acid (UDCA)", NCT03602560) [45]. Unfortunately, the open-label extension phase of this study was suspended after the onset of a similar trial evaluating the role of Seladelpar in NASH that found the occurrence of interface hepatitis in histological specimens. However, an independent panel of expert hepatologists and pathologists deemed that study-stopping was not warranted, since liver injury was within the expected changes seen in NASH patients and could not be attributed to Seladelpar. Recruitment has therefore restarted for Seadelpar in PBC patients after being put on hold. The phase 3 RESPONSE trial (NCT04620733) is currently recruiting patients.

Elafibranor, a dual PPAR-α/δ agonist, also studied in non-alcoholic steatohepatitis (NASH) [47], was recently tested in a multicenter, randomized, double-blind, placebocontrolled phase 2 study clinical trial recruiting patients with PBC non-responders to UDCA. Data were discussed at the International Liver Congress in Vienna in April 2019 [36]. Fortyfive patients were randomized into three arms: Elafibranor 80 mg, Elafibranor 120 mg, and placebo. After 12 weeks of treatment, a reduction in ALP from baseline was observed in 48% patients in the 80 mg group and in 41% in the 120 mg arm; an increase of 3% was detected with placebo. Moreover, 67% patients in the 80 mg group (*p* = 0.001) and 79% of patients in the 120 mg group (*p* < 0.001) reached the secondary endpoint (serum ALP < 1.67 ULN, ALP decrease > 15%, total bilirubin < ULN) (NCT03124108). Thus, in July 2019, the USA FDA and the European Medicines Agency approved Orphan Drug Designation to Elafibranor for the treatment of PBC [48].


**2. Materials and Methods**

Hybrid Intelligence Systems include several strategies with the goal of enhancing the capabilities of either the human, the machine or both of them. A taxonomy has been proposed based on the task characteristics, learning paradigm, AI-Human interaction, and Human-AI interaction [3].

We describe below several techniques that can be grouped under the term Human-inthe-Loop Machine Learning (HITL-ML), and can be applied between others, to the Cancer prognosis and diagnosis scenarios, where training samples are scarce and domain expert knowledge is expensive.