Which of the following factors does not contribute directly to the bystander effect according to research on this topic?

The Bystander

In addition to the bully and the bullied (bully-victim), there is often the bystander. Bullying interaction occurs once every seven minutes, with teachers rarely intervening in what they witness. In addition, in 88 percent of bullying incidents, peers are present (Morrison 2011)6 . These powerful statistics reveal that a quick change in staff behavior can have a monumental impact. Interestingly, Morrison also states that in the majority of bullying episodes where peers are present and witness the behavior, the more likely it is that the bullying episode will be extended. However, in the majority of episodes (57 percent), peer intervention stops bullying within ten seconds, regardless of strategy.

For a better understanding of the bystander effect and its pervasiveness amongst both staff and students, consider the following two enlightening, research-based texts: 1) Barbara Coloroso’s The Bully, the Bullied, and the Bystander, and 2) Prior Knowledge of Potential School-Based Violence: Information Students Learn May Prevent a Targeted Attack, US Secret Service and the US Department of Education (free online on at http://www.secretservice.gov/ntac/bystander_study.pdf). Also known as “The Bystander Study,” this latter resource represents the third and final release from the collaborative research of the above stated agencies. The initial study, The Safe School Initiative, revealed ten key findings applicable to the bullying discussion:7

Incidents of targeted violence at schools rarely were sudden impulsive acts.

Prior to most incidents, other people knew about the attacker’s idea and/or plan to attack.

Most attackers did not threaten their targets directly prior to advancing the attack.

There was no useful or accurate “profile” of students who engaged in targeted school violence.

Most attackers engaged in some behavior prior to the incident that caused others concerns or indicated a need for help.

Most attackers had difficulty coping with significant losses or personal failures.

Moreover, many attackers had considered or attempted suicide.

Many attackers felt bullied, persecuted, or injured by others prior to the attack.

Most attackers had access to and had used weapons prior to the attack.

Despite prompt law enforcement responses, most shooting incidents were stopped by means other than law enforcement interventions.

Specific immune modulators

Ideally we need drugs that would preserve the immune responses directed against the microbial pathogen but downregulate the bystander effects on the surrounding brain tissue. This can only be accomplished if we develop a better understanding of the underlying pathophysiologic mechanisms that mediate these immune responses. However, for some infections such as cryptococcal infection we need to develop better mechanisms to clear the antigen from the CNS, since current fungicidal agents may kill the pathogen but the antigen may remain in the CNS and intrathecal space for months, thus driving the immune response. In HIV-infected patients, where the inflammation is triggered by the Tat protein despite the use of adequate cART, agents need to be developed that will block the production of Tat or antagonize its effects on the HIV long terminal repeat and thus drive it along protein degradation pathways.

CNTF-derived neurogenic/neurotrophic compound, P021, can exert a disease-modifying effect in a transgenic mouse model of AD

A widely prevalent hypothesis regarding the role of neural stem cells–based therapy for neurological disorders is that of the “bystander” effect mechanism of neural stem cells, that is, neural stem cells can improve function by providing missing or defective enzymes or modulating function or may preserve endogenous neuronal function by providing neurotrophic support (Martino and Pluchino, 2006; Redmond et al., 2007). A study demonstrated that transplantation of neuronal precursor cells in transgenic mice expressing human P301S tau protein exerted a neuroprotective effect by release of growth factors including CNTF, nerve growth factor, and glia-derived neurotrophic factor (Spillantini et al., 2011). Another study showed that hippocampal neural stem cell transplantation improved cognition and enhanced hippocampal synaptic density via BDNF without affecting Aβ or tau pathology in 3×Tg-AD mice (Blurton-Jones et al., 2009). However, few other studies have demonstrated that neural stem cells or neural precursor cell implantation or enhancement of endogenous BDNF expression can exert a disease-modifying effect in AD (Corona et al., 2010; Dobarro et al., 2013a,b; Kern et al., 2011; Lahiani-Cohen et al., 2011; Rachubinski et al., 2012).

In a study, we treated 9–10-month-old 3×Tg-AD mice with P021 for 12 months and found that pharmacological stimulation of neural stem cells by chronic treatment with this neurotrophic peptidergic compound not only rectified deficits in neurogenesis, neuronal and synaptic plasticity, and cognition but also reduced the underlying disease pathology (Kazim et al., 2014). The study results were quite exciting as they provided evidence that a neurotrophic factor small molecule mimetic can reduce tau and Aβ pathologies (Figs. 2.3 and 2.4) rather than exerting a mere “bystander” effect by virtue of enhanced neurogenesis and neuronal plasticity.

The compound P021 has plasma half-life of >3 h and stability of >95 and >90% in artificial intestinal fluid for 2 h and in artificial gastric juice for 30 min, respectively (Kazim et al., 2014). P021 is BBB permeable and thus this small molecule mimetic overcomes the main limitation associated with therapeutic usage of neurotrophic factors, such as CNTF and BDNF. Up to 1 year of administration of P021 did not show any undesirable side effects in 3×Tg-AD or control mice (Kazim et al., 2014). Unlike recombinant CNTF, which was reported to cause anorexia, skeletal muscle loss, hyperalgesia, severe cramps, and muscle pain in humans (ACTSG, 1996), we did not observe any alteration in the general physical state, including body weight, grooming, posture, and clasping reflex in P021-treated animals (Kazim et al., 2014). The P021 treatment had no significant effect on anxiety and level of exploration in mice (Kazim et al., 2014).

P021 is the first neurotrophic compound that can rescue not only deficits in neurogenesis and neuronal plasticity but also robustly attenuate tau pathology and partly reduce Aβ pathology and rescue cognitive impairment in 3×Tg-AD mice at moderate to severe stages of disease. Based on our primary neuronal culture and mouse model studies, we have found that the disease-modifying effect of P021 is due to increased BDNF expression–mediated decrease in GSK3β activity (Fig. 2.5). Increased BDNF expression is known to activate PI3K-AKT signaling that results in downstream inhibition of GSK3β activity by increase in its inhibitory phosphorylation at Ser9 by AKT (Corona et al., 2010; Cuadrado-Tejedor et al., 2011; Dobarro et al., 2013a,b; Elliott et al., 2005; Lahiani-Cohen et al., 2011). GSK3β is a major tau serine/threonine kinase, which phosphorylates tau at many different sites including Ser199, Ser202, Thr205, Ser396, and Ser404 (Wang et al., 1998, 2007). Reduction in GSK3β activity has also been reported to reduce Aβ pathology because of the reduction in amyloidogenic processing of APP (DaRocha-Souto et al., 2012; Sereno et al., 2009).

2.3 “Bystander” Effects

A particular form of the neuroprotective mechanism of functional activity has recently become popular, viz. the attribution of graft efficacy to a “bystander effect.” This term is applied to situations where a graft is seen to exert a functional benefit even in the absence of survival of the grafted cells, as for the adrenal medulla studies from an earlier generation, described earlier. It has become particularly popular in the context of mesenchymal stem cell (MSC) grafts and related multipotent cell types, often with peripheral administration and putative homing to a dysfunctional target. Significant recovery, typically with rapid onset, has been reported in animal models of neuroinflammation (Einstein et al., 2007; Martino and Pluchino, 2006), stroke (Bacigaluppi et al., 2009), demyelination (Uccelli and Mancardi, 2010), brain trauma (Tajiri et al., 2013), and spinal cord injury but where long-term survival of the migrating cells cannot be detected. Such observations in the CNS are mirrored by the hypothesized mechanisms of MSC therapy in other organ systems also, such as cardiac repair (Lai et al., 2011).

To address these effects, a major focus of recent experimental research has been on the potential of neural stem/precursor cells to protect the CNS from inflammatory damage. In a major influential review, Martino and Pluchino (2006) have postulated a basis for the bystander effect in the response of neural stem/precursor cells to respond to inflammatory regulators and modulate the host inflammatory response. Thus, undifferentiated neural stem cells are responsive to a similar wide range of stem cell regulators, inflammatory mediators, and growth factors as are the cells implicated in inflammatory conditions including experimental allergic encephalomyelitis (EAE) and human autoimmune disease, such as multiple sclerosis (MS). The immature grafted precursor cells are considered to exert a neuroprotective influence on slowly evolving neurodegenerative processes by dissipating host inflammatory reactions, reducing glial scar formation, and inhibiting apoptotic cell death pathways (Bacigaluppi et al., 2009).

The optimism surrounding the “bystander” phenomenon with the promise of an effective therapy even when the grafted cells do not survive, and the mechanism of action remains unspecified, is in danger of encouraging a premature rush to clinical application (Doeppner and Hermann, 2014; Mack, 2011). However in a recent review, Martino (2016) concludes that “until the basic mechanisms that regulate stem cell function are determined, all triumph is misplaced.” In the context of a more widespread concern about current trends to unregulated stem cell tourism (Kiatpongsan and Sipp, 2009), the emphasis of all credible research programs should be not only on well-conducted clinical research maintaining international trial standards, but also on the detailed basic research to unravel the mechanisms of any effects.

11 Functional Evidence from Mouse Genetics

While there is mounting evidence for cerebellar phenotypes in mouse mutants for autism genes as discussed above, it remains controversial whether these are a bystander effect or are key to the disease pathogenesis. Using conditional mouse knockouts for TSC proteins, recent studies have provided functional evidence that abnormal PC function is an important contributor to autism-related behavior in the mouse. TSC is an autosomal-dominant disorder with high rates of comorbid ASD caused by mutations in either TSC1 or TSC2. As discussed above, the cerebellum has been implicated in TSC, and cerebellar pathology is correlated with the severity of ASD symptoms in TSC patients (Eluvathingal et al., 2006; Weber et al., 2000). Tsc1 and Tsc2 are strongly expressed in the mouse cerebellum (Gutmann et al., 2000). To investigate the contribution of cerebellar TSC1 to autistic-like behavior in a mouse model, Tsai et al. (2012) created conditional mouse mutants with Tsc1 deleted only in PCs (Tsc1PC). PC-specific loss of Tsc1 results not only in progressive ataxia but also causes autistic-like behaviors including impaired social interaction, repetitive behavior, and abnormal ultrasonic vocalizations. Interestingly, the Tsc1PC heterozygote mice, which more accurately mimic the human genetic condition, display no motor impairments but similar social deficits compared to the homozygous Tsc1PC knockout mice, suggesting that motor deficits are not responsible for the abnormal social behavior. On a cellular level, Tsc1-deficient PCs exhibit abnormal spine density and reduced excitability. Furthermore, progressive loss of PCs occurs in the homozygous mice, likely causing the observed motor impairments. It will be important to determine whether cerebellar output from the cerebellar nuclei is reduced and also which connections to other brain structures are affected in the Tsc1PC-deficient mice. This will give important insights into the cerebello-cortical circuitry underlying the observed autism-related behaviors.

Similar findings were observed upon deletion of Tsc2, specifically in PCs. Homo- and heterozygous Tsc2PC mutant mice display PC degeneration and motor impairment (Reith et al., 2011). Furthermore, heterozygous Tsc2PC-deficent mice show autistic-like behavior including increased repetitive behavior and social deficits (Reith et al., 2013).

TSC1 and TSC2 are known to negatively regulate the mammalian target of rapamycin (mTOR) signaling. Importantly, the pathological and behavioral deficits in the Tsc1PC- and Tsc2PC-deficient mice are prevented upon treatment of the mice with the mTOR inhibitor rapamycin (Reith et al., 2011, 2013; Tsai et al., 2012), identifying the mTOR signaling pathway as a key molecular mechanism in the cerebellum contributing to autistic-like behavior.

Introduction

Social influence is ubiquitous in human societies. It takes a wide variety of forms, including obedience, conformity, persuasion, social loafing, social facilitation, deindividuation, observer effect, bystander effect, and peer pressure. Research on social influence has a long history in social psychology, and an experiment on social facilitation effect that was conducted in 1898 by Triplett [1] is often considered the first social psychological experiment (see also Ref. [2]). Since then, social influence has fascinated scholars in various fields.

Since 2005, researchers in the emerging and growing fields of social neuroscience, neuroeconomics, and neuromarketing have begun to explore the neural bases of such complex social phenomena using methods in cognitive neuroscience including functional magnetic resonance imaging (fMRI), electroencephalography (EEG), and transcranial magnetic stimulation (TMS). In this chapter, I will cover social neuroscience and neuroeconomics studies investigating the following two forms of social influence: (1) the effect of others' presence on prosocial behavior (observer effect) and (2) the effect of others' opinion on an individual's preference (social conformity). Both the observer effect and social conformity can be considered primary examples of social influence, as they represent two of the most relevant and ubiquitous forms of social influence in our everyday social lives.

The Use of Deception

Sometimes researchers must use deception in their research. In these cases, if the participants have knowledge of the purpose or procedures of the study, the study results will not be interpretable. For example, studies of the “bystander effect” investigate whether people will help others if they observe them experiencing a harmful or dangerous situation. The researchers cannot generally tell the participants that the researchers are studying whether people will act in an empathic way toward a bystander. This knowledge would likely change the participants’ behavior. And it would be impossible to tell if the participants acted the way they did because they had empathy or because they knew they were being observed.

Therefore, researchers will provide a cover story to explain the study.

When researchers use deception, they must justify the need for deception. The IRB will carefully examine that the benefits of deception outweigh the risks. Researchers must document that the study could not be done without deception. This is critical, since it is not possible to give full informed consent if you do not know what the purpose of the study is. Therefore, at the end of the study, the investigators debrief the participants and provide information about the true nature of the study. And they discuss the participants' reactions to the deception.

Senescent cell bystander effects

With the myriad of bioactive (SASP) molecules secreted by senescent cells, strong paracrine effects of senescence are no surprise. In fact, Campisi’s group showed already in 2001 that senescent somatic cells stimulated growth and invasion of tumor cells (Krtolica, Parrinello, Lockett, Desprez, & Campisi, 2001), and this has been confirmed by multiple groups since (Rao & Jackson, 2016; Saleh et al., 2018). We discovered in 2012 that senescent cells also had a paracrine effect on normal, somatic cells—they induced senescence as a bystander effect (Nelson et al., 2012). This was soon confirmed by others (Acosta et al., 2013). Not dissimilar to the situation with radiation-induced bystander effects in cancer therapy (Wang, Zhou, Liu, & Zuo, 2018), the quest to identify specific, individual components of the secretome as mediators of the senescent bystander effect has been elusive. Multiple interventions targeting ROS, NF-κB activity, mTORC1 signaling, or p38MAPK activity were all capable of suppressing the bystander effect, but SAMD-derived ROS appeared to be upstream of the NF-κB-mediated proinflammatory SASP (Nelson et al., 2018). Weak bystander effects seemed dependent on cell–cell contacts via gap junctions, as they could efficiently be blocked by octanol, a disruptor of such contacts (Nelson et al., 2012).

Recently, the role of bystander-induced senescence for the accumulation of senescent cells and their functional consequences in vivo has been delineated: after transplanting very low numbers of senescent cells into either the muscle or skin of mice, enhanced frequencies of tissue-resident senescent cells were detected adjacent to the transplanted cells (da Silva et al., 2019). When slightly higher numbers of senescent cells were transplanted into fat depots, senescence spread into peripheral organs and persistent physical dysfunction was induced. With old mice as recipients, both mean lifespan and healthspan were reduced. These effects could be blocked by senolytic treatment following transplantation, indicating the causal role of the senescence-induced bystander effect (Xu et al., 2018).

Senescent cells accumulate in many tissues with age, and the rate of accumulation, at least in some tissues, predicts lifespan in mice (Jurk et al., 2014). Decreasing efficiency of immunosurveillance is one of the causes of age-associated accumulation of senescent cells (Ovadya et al., 2018), while the spread of senescence via bystander signaling is another. This was tested by comparing accumulation rates of senescent cells in wild-type and severely immunodeficient NOD scid gamma (NSG) mice under both ad libitum and dietary-restricted feeding (da Silva et al., 2019). As expected, senescent cells accumulated much faster in NSG mice fed ad libitum in agreement with the absence of a functional immune system. Suppressing the SASP (and thus the bystander effect) by dietary restriction slowed down the accumulation of senescent cells in the NSG mice, but resulted in a net loss (a senolytic effect, see section "Senolytics and senostatics as antiaging interventions") in the immunocompetent wild-type mice (da Silva et al., 2019). These data suggest that immunosurveillance and the bystander effect are the two major partners that determine the rate of accumulation of senescent cells in vivo in a dynamic equilibrium.

Implications for sport psychologists

Based on the knowledge that one has today, what should the implications for sport psychologists and sport psychology consultants be? Whatever the valid prevalence numbers are, statistically, sport psychologists are highly likely to be working with athletes who have been or are harassed or abused. Some may have treated victims or survivors, but some may also never have learned about their athletes’ harassing and abusive experiences, though they may have had their suspicions. If knowledge about harassment and abuse never were in their training when becoming a sport psychologist or sport psychology consultants, they may not be able to see the signs, simply because they never did learn about it. In searching the literature, surprisingly few articles have written about the role of sport psychologists in preventing and treating harassed and abused athletes. Some of the few are from Trisha Leahy (2010a,b, 2011) from Hong Kong and from Ashley Stirling and Gretchen Kerr (2010) from Canada. In the following I draw heavily upon their work. All authors stress that the sport psychologists, because of their close involvement with a team, are often the first point of contact for athletes in distress, and thus need to be aware of the relevant social policy and procedures for reporting and referring. As gatekeepers for athletes’ safety in identifying, intervening, and acting to prevent the sexual abuse of athletes in sport systems, the sport psychologists have a key safeguarding role (Leahy, 2010a). Leahy writes that “Implications for sport psychology practice involve individual assessment and intervention as well as, more generally, training and supervision programs for sport psychologists” (Leahy, 2011, p. 260), and that the implications for psychology practice may be understood as operating at both an individual and systemic level.

Concerning the individual level, assessment and treatment of athlete survivors of childhood sexual abuse implies that training programs for sport psychologists need to include comprehensive education in the assessment and treatment of childhood abuse and traumagenic symptomatology. Leahy (2011) also stresses that the sport psychology profession should become a more socially engaged discipline. This is embedded in the systemic issues when she refers to the necessity to be aware of the sociocultural context of organized competitive sport, which in some countries has been criticized for normalizing psychologically abusive coaching practice, particularly in relation to children and youth (Brackenridge, 2001; Leahy et al., 2004). The implications of this is the necessity of changing these accepted coaching styles, which masks sexual offender behaviors that rely on psychological abuse and emotional manipulation as primary strategies. A hierarchical power structure has also been found to be associated with the bystander effect, in which observing adults feel unable to intervene in high-risk or suspicious circumstances. The bystander effect may be a result of such an environment, and to overcome this, comprehensive and ongoing sexual abuse awareness education is imperative for all those involved in organized sport, not only the psychologist, but also athletes, parents, and other people, among the support personnel. Leahy (2011, p. 255) also writes that:

Before sport psychologists can step up to the role of gatekeeper, effectively acting to protect the rights of young people in sport, we must first insist on our own rights to be educated and provided with clear ethical guidelines and core competencies embedded in a support system that empowers us to act on behalf of young athletes at risk.

She stresses, however, that sport psychology training programs that primarily teach mental skills as performance enhancement techniques at the expense of training in related systemic policy, advocacy, and ethical systems will not “equip entrants to the profession with the necessary competencies to enable effective engagement with a biopsychosocial discourse and praxis” (Leahy, 2010a, p. 319).

Stirling and Kerr (2010) did a study with the purpose of assessing the experiences and perceived knowledge base for sport psychology consultants with respect to issue of child protection. Questions of interest included: “Are sport psychology consultants exposed to cases of child maltreatment in sport?,” “Do sport psychology consultants believe they have the requisite knowledge and training to identify the various forms of relational maltreatment?,” and “How might sport psychology consultants be better enabled to act as agents of child protection in sport?” (Stirling & Kerr, 2010, pp. 306–307). They used a mixed method research design where 75 sport psychology consultants completed a questionnaire. In addition, they did eight expert interviews.

The sport psychology consultants were also asked to rank their current knowledge of child protection policies in sport; about half reported “moderate” understanding, and 22% low understanding. Almost all also felt that they were aware of their duty to report incidences of child abuse, including both when and where they should report. The importance of knowledge, training, and competence about children, and of understanding warning signs, symptoms, and specific behaviors associated with child abuse were highlighted by many of the participants. One of them expressed it this way: “We need to know the legal and ethical ramifications and the potential psychological signs and not just be bystanders if at all possible” (Stirling & Kerr, 2010, p. 311). The majority of the participants also suggested supplemental education on athlete/child protection. Many proposed that information on child protection should be provided along with education on other ethical issues faced in the sport environment. The sport psychology consultants also talked about the need for child protection guidelines along with sport-specific examples of maltreatment and best practice in sport, accreditation in counseling ethics as a component of the SPC certification process, and the facilitation of discussion groups where case studies could be discussed with other professionals. The authors summarize the results concerning the recommendations in the following way:

Regardless of the perceived prevalence of abusive or neglectful incidences in sport reported by the SPC’s, the vast majority of the respondents reported that issues of child protection must be addressed by the community of sport psychology professionals. One expert SPC explained, “I don’t think we do enough in terms of thinking outside of psychology skills. We need to think about the bigger picture of how we can protect children from a number of different types of abuse.” (Stirling & Kerr, 2010, p. 312)

The analysis also revealed an inconsistency between the participants’ reports of exposure to specific examples of abusive behaviors in sport and their reported exposure to the various forms of maltreatments. The authors therefore conclude that although the majority of consultants believe they are able to detect abusive and neglectful behaviors, this may not be the case and therefore indicated the need for further education about maltreatment and the behavioral constituents of each form of abuse.

The role and the work of sport psychologists and sport psychology consultants vary internationally. I will end this chapter by telling you a case story of how psychologists can work at a major sports event to both prevent and solve problematic issues that may occur. This is from the 2nd African Youth Games that were held in Gabarone, Botswana, in May 2014. The games had 2500 participants of both genders from all of the 54 African countries. The organizing committee of the games and the Norwegian Olympic and Paralympic Committee and Confederation of Sports (NIF) initiated a partnership to provide safety planning and establish precedence for the hosting of the games under a “safe games” theme (Huffman, 2014). Sport safety planning was defined as being aware, prepared, and active in promoting a Safe Games environment for players, coaches, officials, volunteers, and spectators. Many different actions were taken, but for this chapter I will only present the psychological services that were provided. In reading this, you should have in mind that it is not common in most African countries that psychologists are working with sport teams. In this case, contact was taken with the University of Botswana’s Counselling Services Department. Together with The Botswana Association of Psychologists, and Childline, they developed a support and reporting system for the Games. Elements included were, for example, “Safe Games Reporting Box” in different locations throughout the athlete’s village, a direct toll-free emergency call number, direct reporting to the psychologists at the place or the clinic, and participation by the psychologists at the daily chef du mission meetings where challenges were brought forward. The University of Botswana provided the venue and the staff for securing a confidential and professional service to the Games’ participants. The group, which consisted of 38 people mostly psychologists and a few sociologists, called themselves “Safe Games Psychological First Aiders.” There was a lot of aggression and violence going on and as an example of one of the things that the psychologist did was that they briefed the full medical team on abuse and child/youth safeguarding—recognizing signs of stress and abuse. The psychological First Aiders were assigned to different areas throughout the Games’ 24 h, including competition venues, the athletes’ village and residences. There were always three members of the team at the counseling clinic, and counseling services were provided for everyone. One person was assigned to roam all areas and carried a radio linked to the medical unit and police. The psychological team members were on alert all the time, and if they observed an abusive or potentially abusive situation, they would identify themselves and be available to calm a difficult situation before it became a major problem. They also had sessions with a whole team based on the reaction of coaches and athletes during the competitions on request from a team leader to assist with the levels of stress and anxiety. The main problems identified were related to stress and anger due to pressure to perform, but there were a high number of reports of abuse, particularly verbal abuse, to staff and volunteers, incidents that were managed by the Safe Games’ Psychological First Aiders. They provided a number of interventions during the games for different individuals and teams including interviews; relaxation exercises; motivational workshops as requested by coaches, team leaders, or team attachés; counseling sessions; calming techniques; conflict resolution; and anger management. According to Diane Huffman from NIF who reported on the safe guarding of the Games, “an important result was the understanding by all parties of the value and need of such services at major Games where anxiety and stress levels are high” (Huffman, 2014, p. 2). She also writes that based on the experiences from these Games, The Botswana Association of Psychologists and the Botswana National Sports Council are now considering a proposal to work together and provide awareness problems and support systems to the sport associations of Botswana on an ongoing basis.

Based on the few publications presented in this last section, it is clear that the sport psychologists are in a unique position to protect, discover, hinder, and treat athletes from sexually harassing and abusive behaviors. But some prerequisites are necessary. First of all, the sport psychologist must have the necessary knowledge about what constitutes the different forms of harassment and abuse. Second, he or she should work in an environment that has policies for protecting not only the athletes, but also the people who are accused of GSHA, which theoretically could be a sport psychologist. Until a case has been researched and solved either by the sport organization itself or in a criminal court, it is important to have a system in place that take care of both parts. There is no research or statistics in sport about false accusations, and research outside sport is also very scarce. But it is of great importance that ethical guidelines are developed for everyone involved in sport. Such guidelines should also include guidelines for reporting and how cases should be taken care of. If policies and guidelines do not exist, the sport psychologists, if part of the athletes’ entourage, should push for and see to that the sport club or association get it. By not being a bystander, but taking action when they observe or have suspicions about the occurrence of harassment and abuse, sport psychologists can and should play an important role in creating a safer sport environment for everyone involved in sport.

Both ISSP and FEPSAC have position statements related to violence in sport. ISSP (n.d.) is the oldest. It is titled “Aggression and Violence in Sport.” It seems to have been written many years ago, and concerns primarily aggression as indicated in the title. It barely touches upon the problems described in this chapter. As previously mentioned, the role of the sport psychologists is important, and ISSP should therefore develop and decide upon a position statement in which the problems related to SHA in sport are much better addressed. FEPSAC (2002), on the other hand, has a position statement (# 6) on sexual exploitation in sport. With respect to what has been presented in this chapter, every paragraph is still relevant, but it could be somewhat broadened and updated based on the research that has taken place since it was written. This concerns different types of harassment and abuse, including neglect and hazing; a clearer separation between the child and adult athlete; a stronger focus on peer harassment and abuse; and the role of the sport psychologists in the prevention of the occurrence of such behavior. FEPSAC (2011) also decided upon a position statement (# 9) about ethical principles of the European Sport Psychology Federation. These are very relevant both for research on and treatment of athletes who have experienced SHA. A referral to this position statement could also be done in position statement (# 6) as previously mentioned. Together, if these positions are put into practice, that is, followed by the members of FEPSAC, the organization may be an important contributor in making sport a safer place for everyone.

Gene therapy

The most prominent hallmark in the HCC therapeutics which has shown remarkable achievements in the antitumor effect in humans is suicide gene therapy. This therapeutic is dependent on trangenes delivery and further converting them into prodrugs and their route of administration is through gene delivery into cytotoxic metabolites [66]. The peculiarity of suicide gene therapy is during cytotoxicity cell-to-cell contact caused bystander effect in tumor microenvironment which further inhibits the tumor cells [67]. Kemeny et al. [68] introduced Ganciclovir and Wills et al. [69] reported herpes simplex virus thymidine kinase (HSV-tk), which are the two major combinations of transgenes and prodrugs which are mostly used in the treatment of HCC gene therapy. In clinical trial testing, through adenoviral vector gene delivery of HSV-tk is by intravenous (NCT02202564, NCT00300521, and NCT03313596) or intratumoral (NCT00844623) injection. To insert the suicide gene in tumor cells, genome editing approach has been used to target the genomic rearrangement [70]. To target the retroviral replicating vectors using transcriptional process, suicide gene needs to be elicited in tumor-specific manner [71].

Yamada et al. [72] have been reported oncolytic virotherapy for showing its antitumor effect in HCC and many others human body cancers, including in colorectal cancer at metastatic stage delivery of oncolytic herpes simplex virus type-1 injected via hepatic artery (NV1020, NCT00012155) and in primary liver cancer (NV1020, NCT00012155). An immunotoxin-diphtheria toxin A, one of the potential gene targets, works to inhibit the protein synthesis in gene therapy [73], pancreatic cancer [74,75], glioblastoma [76], bladder cancer [77], and ovarian cancer studied by Amit and Hochberg [76] and Mizrahi et al. [78]. For gene therapy several gene delivery methods are used via plasmid DNA (ovarian, bladder, and pancreatic cancer) and integrase–deficient lentiviral vector (protein synthesis inhibition).