Physical Activity Decreases Inflammation and Delays Development of Obesity-Associated Pancreatic Ductal Adenocarcinoma.

Obesity is a risk factor for pancreatic ductal adenocarcinoma (PDAC), a deadly disease with limited preventive strategies. Lifestyle interventions to decrease obesity represent a potential approach to prevent obesity-associated PDAC. Here, we examined whether decreasing obesity through physical activity (PA) and/or dietary changes could decrease inflammation in humans and prevent obesity-associated PDAC in mice. Comparison of circulating inflammatory-associated cytokines in subjects (overweight and obese) before and after a PA intervention revealed PA lowered systemic inflammatory cytokines. Mice with pancreatic-specific inducible KrasG12D expression were exposed to PA and/or dietary interventions during and after obesity-associated cancer initiation. In mice with concurrent diet-induced obesity (DIO) and KrasG12D expression, the PA intervention led to lower weight gain, suppressed systemic inflammation, delayed tumor progression, and decreased pro-inflammatory signals in the adipose tissue. However, these benefits were not as evident when obesity preceded pancreatic KrasG12D expression. Combining PA with diet-induced weight loss (DI-WL) delayed obesity-associated PDAC progression in the genetically engineered mouse model, but neither PA alone nor combined with DI-WL or chemotherapy prevented PDAC tumor growth in orthotopic PDAC models regardless of obesity status. PA led to upregulation of IL-15ra in adipose tissue. Adipose-specific overexpression of IL-15 slowed PDAC growth but only in non-obese mice. Overall, our study suggests that PA alone or combined with DI-WL can reduce inflammation and delay obesity-associated PDAC development or progression. Lifestyle interventions that prevent or manage obesity or therapies that target weight loss-related molecular pathways could prevent progression of PDAC.

Identification of group differences in predictive anticipatory biasing of pain during uncertainty: preparing for the worst but hoping for the best.

ABSTRACT: Pain anticipation during conditions of uncertainty can unveil intrinsic biases, and understanding these biases can guide pain treatment interventions. This study used machine learning and functional magnetic resonance imaging to predict anticipatory responses in a pain anticipation experiment. One hundred forty-seven participants that included healthy controls (n = 57) and individuals with current and/or past mental health diagnosis (n = 90) received cues indicating upcoming pain stimuli: 2 cues predicted high and low temperatures, while a third cue introduced uncertainty. Accurate differentiation of neural patterns associated with specific anticipatory conditions was observed, involving activation in the anterior short gyrus of the insula and the nucleus accumbens. Three distinct response profiles emerged: subjects with a negative bias towards high pain anticipation, those with a positive bias towards low pain anticipation, and individuals whose predictions during uncertainty were unbiased. These profiles remained stable over one year, were consistent across diagnosed psychopathologies, and correlated with cognitive coping styles and underlying insula anatomy. The findings suggest that individualized and stable pain anticipation occurs in uncertain conditions.

Psychedelics in Addiction Treatment-Navigating a Sociopolitical Rift.

This Viewpoint discusses the use of psychedelics in treatment for substance use disorders.

Psychedelic therapies reconsidered: compounds, clinical indications, and cautious optimism.

The clinical investigation of psychedelic medicines has blossomed over the last 5 years. Data from a Phase 3 industry trial and a multicenter Phase 2 industry trial, in addition to multiple early phase investigator-initiated and industry trials, have now been published in peer-reviewed journals. This narrative review summarizes both the recent data and the current clinical trials that are being conducted with various classes of "psyche-manifesting" substances, which may prove beneficial in the treatment of a broad range of conditions. Methodological considerations, unique challenges, and next steps for research are discussed in keeping with the uniquely "experiential" nature of these therapies.

MDMA-assisted therapy for moderate to severe PTSD: a randomized, placebo-controlled phase 3 trial.

This multi-site, randomized, double-blind, confirmatory phase 3 study evaluated the efficacy and safety of 3,4-methylenedioxymethamphetamine-assisted therapy (MDMA-AT) versus placebo with identical therapy in participants with moderate to severe post-traumatic stress disorder (PTSD). Changes in Clinician-Administered PTSD Scale for DSM-5 (CAPS-5) total severity score (primary endpoint) and Sheehan Disability Scale (SDS) functional impairment score (key secondary endpoint) were assessed by blinded independent assessors. Participants were randomized to MDMA-AT (n = 53) or placebo with therapy (n = 51). Overall, 26.9% (28/104) of participants had moderate PTSD, and 73.1% (76/104) of participants had severe PTSD. Participants were ethnoracially diverse: 28 of 104 (26.9%) identified as Hispanic/Latino, and 35 of 104 (33.7%) identified as other than White. Least squares (LS) mean change in CAPS-5 score (95% confidence interval (CI)) was -23.7 (-26.94, -20.44) for MDMA-AT versus -14.8 (-18.28, -11.28) for placebo with therapy (P < 0.001, d = 0.7). LS mean change in SDS score (95% CI) was -3.3 (-4.03, -2.60) for MDMA-AT versus -2.1 (-2.89, -1.33) for placebo with therapy (P = 0.03, d = 0.4). Seven participants had a severe treatment emergent adverse event (TEAE) (MDMA-AT, n = 5 (9.4%); placebo with therapy, n = 2 (3.9%)). There were no deaths or serious TEAEs. These data suggest that MDMA-AT reduced PTSD symptoms and functional impairment in a diverse population with moderate to severe PTSD and was generally well tolerated. ClinicalTrials.gov identifier: NCT04077437 .

MDMA-Assisted Therapy for Severe PTSD: A Randomized, Double-Blind, Placebo-Controlled Phase 3 Study.

Post-traumatic stress disorder (PTSD) presents a major public health problem for which currently available treatments are modestly effective. We report the findings of a randomized, double-blind, placebo-controlled, multi-site phase 3 clinical trial (NCT03537014) to test the efficacy and safety of 3,4-methylenedioxymethamphetamine (MDMA)-assisted therapy for the treatment of patients with severe PTSD, including those with common comorbidities such as dissociation, depression, a history of alcohol and substance use disorders, and childhood trauma. After psychiatric medication washout, participants (n = 90) were randomized 1:1 to receive manualized therapy with MDMA or with placebo, combined with three preparatory and nine integrative therapy sessions. PTSD symptoms, measured with the Clinician-Administered PTSD Scale for DSM-5 (CAPS-5, the primary endpoint), and functional impairment, measured with the Sheehan Disability Scale (SDS, the secondary endpoint) were assessed at baseline and at 2 months after the last experimental session. Adverse events and suicidality were tracked throughout the study. MDMA was found to induce significant and robust attenuation in CAPS-5 score compared with placebo (P < 0.0001, d = 0.91) and to significantly decrease the SDS total score (P = 0.0116, d = 0.43). The mean change in CAPS-5 scores in participants completing treatment was -24.4 (s.d. 11.6) in the MDMA group and -13.9 (s.d. 11.5) in the placebo group. MDMA did not induce adverse events of abuse potential, suicidality or QT prolongation. These data indicate that, compared with manualized therapy with inactive placebo, MDMA-assisted therapy is highly efficacious in individuals with severe PTSD, and treatment is safe and well-tolerated, even in those with comorbidities. We conclude that MDMA-assisted therapy represents a potential breakthrough treatment that merits expedited clinical evaluation. Appeared originally in Nat Med 2021; 27:1025-1033.

Commentary: Evidence-Informed Recommendation to Achieve Approximate Parity in the Allowed Number of Doses for Common Psychedelics.

In recent years, policymakers have proposed and implemented regulatory changes promoting the deprioritization, decriminalization, or state-level legalization of one or more psychedelic substances, usually referencing data from clinical trials as reasons to support liberalizing drug control policies. As psychedelic policies continue to be drafted, personal possession limits may be considered for inclusion in those regulations. If "allowable amount" limits are to be written into law to set personal possession limits, then such amounts should be more consistently related to psychedelic doses found to be safe and efficacious in clinical trials, existing data on moderate-high doses commonly used in various naturalistic settings, and the few studies that estimate psychedelic dose equivalence based on the intensity of subjective effects. In this commentary, we provide an evidence-informed table of typical moderate-high doses for seven commonly used psychedelic substances. These estimates of comparable moderate-high doses can be used to inform "allowable amount" values for psychedelic substances. When such limits are written into legislation, the adoption of evidence-informed comparable limits akin to those presented here would be an important first step toward ensuring greater parity and consistency in drug policy, relative to limits that have little or no scientific basis.

Physical Activity Delays Obesity-Associated Pancreatic Ductal Adenocarcinoma in Mice and Decreases Inflammation.

BACKGROUND & AIMS: Obesity is a risk factor for pancreatic ductal adenocarcinoma (PDAC), a deadly disease with limited preventive strategies. Lifestyle interventions to decrease obesity might prevent obesity-associated PDAC. Here, we examined whether decreasing obesity by increased physical activity (PA) and/or dietary changes would decrease inflammation in humans and prevent PDAC in mice. METHODS: Circulating inflammatory-associated cytokines of overweight and obese subjects before and after a PA intervention were compared. PDAC pre-clinical models were exposed to PA and/or dietary interventions after obesity-associated cancer initiation. Body composition, tumor progression, growth, fibrosis, inflammation, and transcriptomic changes in the adipose tissue were evaluated. RESULTS: PA decreased the levels of systemic inflammatory cytokines in overweight and obese subjects. PDAC mice on a diet-induced obesity (DIO) and PA intervention, had delayed weight gain, decreased systemic inflammation, lower grade pancreatic intraepithelial neoplasia lesions, reduced PDAC incidence, and increased anti-inflammatory signals in the adipose tissue compared to controls. PA had additional cancer prevention benefits when combined with a non-obesogenic diet after DIO. However, weight loss through PA alone or combined with a dietary intervention did not prevent tumor growth in an orthotopic PDAC model. Adipose-specific targeting of interleukin (IL)-15, an anti-inflammatory cytokine induced by PA in the adipose tissue, slowed PDAC growth. CONCLUSIONS: PA alone or combined with diet-induced weight loss delayed the progression of PDAC and reduced systemic and adipose inflammatory signals. Therefore, obesity management via dietary interventions and/or PA, or modulating weight loss related pathways could prevent obesity-associated PDAC in high-risk obese individuals.

Learning from addiction: Craving of prescription opioids in chronic pain sufferers.

Prescription opioids are a primary driver of opioid-related deaths. Although craving is a substantial component of OUD, the degree to which craving leads to misuse among chronic pain patients on long-term prescription opioids is unknown. A clear understanding of the factors that lead to misuse in this vulnerable population is needed for the development of safe and effective practices for opioid taper. This narrative review summarizes the relevant literature on the role of craving in addiction and chronic pain through epidemiological and behavioral studies. The first part of this review examines the role of craving in predicting opioid use/misuse in individuals with chronic pain with and without OUD. The second part covers methods on how craving is evaluated experimentally using both subjective and objective measures and provides related findings. The overall goal of this review is to facilitate the development of a population-specific description of craving in those who use opioids to control chronic pain and to describe how it may be mechanistically linked to patterns of opioid (mis)use.

Correction: Updated cost-effectiveness of MDMA-assisted therapy for the treatment of posttraumatic stress disorder in the United States: Findings from a phase 3 trial.

[This corrects the article DOI: 10.1371/journal.pone.0263252.].

The effects of MDMA-assisted therapy on alcohol and substance use in a phase 3 trial for treatment of severe PTSD.

BACKGROUND: Post-traumatic stress disorder (PTSD) is commonly associated with alcohol and substance use disorders (ASUD). A randomized, placebo-controlled, phase 3 trial demonstrated the safety and efficacy of MDMA-assisted therapy (MDMA-AT) for the treatment of severe PTSD. This analysis explores patterns of alcohol and substance use in patients receiving MDMA-AT compared to placebo plus therapy (Placebo+Therapy). METHODS: Adult participants with severe PTSD (n = 90) were randomized to three blinded trauma-focused therapy sessions with either MDMA-AT or Placebo+Therapy. Eligible participants met DSM-5 criteria for severe PTSD and could meet criteria for mild (current) or moderate (early remission) alcohol or cannabis use disorder; other SUDs were excluded. The current analyses examined outcomes on standardized measures of hazardous alcohol (i.e., Alcohol Use Disorder Identification Test; AUDIT) and drug (i.e., Drug Use Disorder Identification Test; DUDIT) use at baseline prior to randomization and at study termination. RESULTS: There were no treatment group differences in AUDIT or DUDIT scores at baseline. Compared to Placebo+therapy, MDMA-AT was associated with a significantly greater reduction in mean (SD) AUDIT change scores (Δ = -1.02 (3.52) as compared to placebo (Δ = 0.40 (2.70), F (80, 1) = 4.20, p = 0.0436; Hedge's g= .45). Changes in DUDIT scores were not significantly different between treatment groups. CONCLUSIONS: MDMA-AT for severe PTSD may also lead to subclinical improvements in alcohol use. MDMA-AT does not appear to increase risk of illicit drug use. These data provide preliminary evidence to support the development of MDMA-AT as an integrated treatment for co-occurring PTSD and ASUD.

Updated cost-effectiveness of MDMA-assisted therapy for the treatment of posttraumatic stress disorder in the United States: Findings from a phase 3 trial.

BACKGROUND: Severe posttraumatic stress disorder (PTSD) is a prevalent and debilitating condition in the United States. and globally. Using pooled efficacy data from six phase 2 trials, therapy using 3,4-methylenedioxymethamphetamine (MDMA) appeared cost-saving from a payer's perspective. This study updates the cost-effectiveness analysis of this novel therapy using data from a new phase 3 trial, including the incremental cost-effectiveness of the more intensive phase 3 regimen compared with the shorter phase 2 regimen. METHODS: We adapted a previously-published Markov model to portray the costs and health benefits of providing MDMA-assisted therapy (MDMA-AT) to patients with chronic, severe, or extreme PTSD in a recent phase 3 trial, compared with standard care. Inputs were based on trial results and published literature. The trial treated 90 patients with a clinician administered PTSD scale (CAPS-5) total severity score of 35 or greater at baseline, and duration of PTSD symptoms of 6 months or longer. The primary outcome was assessed 8 weeks after the final experimental session. Patients received three 90-minute preparatory psychotherapy sessions, three 8-hour active MDMA or placebo sessions, and nine 90-minute integrative psychotherapy sessions. Our model calculates the per-patient cost of MDMA-AT, net all-cause medical costs, mortality, quality-adjusted life-years (QALYs), and incremental cost-effectiveness ratios (ICERs). We reported results from the U.S. health care payer's perspective for multiple analytic time horizons, (base-case is 30 years), and conducted extensive sensitivity analyses. Costs and QALYs were discounted by 3% annually. Costs were adjusted to 2020 U.S. dollars according to the medical component of the U.S. Bureau of Labor Statistics' Consumer Price Index (CPI). RESULTS: MDMA-AT as conducted in the phase 3 trial costs $11,537 per patient. Compared to standard of care for 1,000 patients, MDMA-AT generates discounted net health care savings of $132.9 million over 30 years, accruing 4,856 QALYs, and averting 61.4 premature deaths. MDMA-AT breaks even on cost at 3.8 years while delivering 887 QALYs. A third MDMA session generates additional medical savings and health benefits compared with a two-session regimen. Hypothetically assuming no savings in health care costs, MDMA-AT has an ICER of $2,384 per QALY gained. CONCLUSIONS: MDMA-AT provided to patients with severe or extreme chronic PTSD is cost-saving from a payer's perspective, while delivering substantial clinical benefit.

Postpubertal spermatogonial stem cell transplantation restores functional sperm production in rhesus monkeys irradiated before and after puberty.

BACKGROUND: Cancer treatment of prepubertal patients impacts future fertility due to the abolition of spermatogonial stem cells (SSCs). In macaques, spermatogenesis could be regenerated by intratesticular transplantation of SSCs, but no studies have involved cytotoxic treatment before puberty and transplantation after puberty, which would be the most likely clinical scenario. OBJECTIVES: To evaluate donor-derived functional sperm production after SSC transplantation to adult monkeys that had received testicular irradiation during the prepubertal period. MATERIALS AND METHODS: We obtained prepubertal testis tissue by unilaterally castrating six prepubertal monkeys and 2 weeks later irradiated the remaining testes with 6.9 Gy. However, because spermatogenic recovery was observed, we irradiated them again 14 months later with 7 Gy. Three of the monkeys were treated with GnRH-antagonist (GnRH-ant) for 8 weeks. The cryopreserved testis cells from the castrated testes were then allogeneically transplanted into the intact testes of all monkeys. Tissues were harvested 10 months later for analyses. RESULTS: In three of the six monkeys, 61%, 38%, and 11% of the epididymal sperm DNA were of the donor genotype. The ability to recover donor-derived sperm production was not enhanced by the GnRH-ant pretreatment. However, the extent of filling seminiferous tubules during the transplantation procedure was correlated with the eventual production of donor spermatozoa. The donor epididymal spermatozoa from the recipient with 61% donor contribution were capable of fertilizing rhesus eggs and forming embryos. Although the transplantation was done into the rete testis, two GnRH-ant-treated monkeys, which did not produce donor-derived epididymal spermatozoa, displayed irregular tubular cords in the interstitium containing testicular spermatozoa derived from the transplanted donor cells. DISCUSSION AND CONCLUSION: The results further support that sperm production can be restored in non-human primates from tissues cryopreserved prior to prepubertal and post-pubertal gonadotoxic treatment by transplantation of these testicular cells after puberty into seminiferous tubules.

MDMA-assisted therapy for severe PTSD: a randomized, double-blind, placebo-controlled phase 3 study.

Post-traumatic stress disorder (PTSD) presents a major public health problem for which currently available treatments are modestly effective. We report the findings of a randomized, double-blind, placebo-controlled, multi-site phase 3 clinical trial (NCT03537014) to test the efficacy and safety of 3,4-methylenedioxymethamphetamine (MDMA)-assisted therapy for the treatment of patients with severe PTSD, including those with common comorbidities such as dissociation, depression, a history of alcohol and substance use disorders, and childhood trauma. After psychiatric medication washout, participants (n = 90) were randomized 1:1 to receive manualized therapy with MDMA or with placebo, combined with three preparatory and nine integrative therapy sessions. PTSD symptoms, measured with the Clinician-Administered PTSD Scale for DSM-5 (CAPS-5, the primary endpoint), and functional impairment, measured with the Sheehan Disability Scale (SDS, the secondary endpoint) were assessed at baseline and at 2 months after the last experimental session. Adverse events and suicidality were tracked throughout the study. MDMA was found to induce significant and robust attenuation in CAPS-5 score compared with placebo (P < 0.0001, d = 0.91) and to significantly decrease the SDS total score (P = 0.0116, d = 0.43). The mean change in CAPS-5 scores in participants completing treatment was -24.4 (s.d. 11.6) in the MDMA group and -13.9 (s.d. 11.5) in the placebo group. MDMA did not induce adverse events of abuse potential, suicidality or QT prolongation. These data indicate that, compared with manualized therapy with inactive placebo, MDMA-assisted therapy is highly efficacious in individuals with severe PTSD, and treatment is safe and well-tolerated, even in those with comorbidities. We conclude that MDMA-assisted therapy represents a potential breakthrough treatment that merits expedited clinical evaluation.

The catechol-O-methyltransferase inhibitor tolcapone modulates alcohol consumption and impulsive choice in alcohol use disorder.

RATIONALE: Individuals suffering from alcohol use disorder (AUD) demonstrate difficulty with decision-making and impulsivity that may be associated with impaired frontal cortical function. Therapeutics that enhance frontal dopamine tone could decrease impulsivity and in turn reduce alcohol consumption in individuals with AUD. OBJECTIVES: To determine if the catechol-O-methyltransferase (COMT) inhibitor tolcapone can attenuate alcohol consumption in individuals with AUD and whether this attenuation correlates with tolcapone-induced changes in laboratory-based decision-making tasks. METHODS: We used daily self-report and a novel group laboratory bar task to assess the effects of randomized double-blind crossover administration of tolcapone (100 mg TID for 5 days) on alcohol consumption and laboratory tasks assessing impulsivity in 55 non-treatment-seeking subjects with AUD. RESULTS: Tolcapone significantly reduced self-reported alcohol consumption (t (54) = 2.05, p = 0.045). The effects of tolcapone on drinking significantly correlated with changes in impulsive decision-making, such that subjects with the greatest decrease in impulsive choice on tolcapone also reported the greatest decrease in alcohol consumption (r (45) = 0.40, p = 0.0053). We did not see effects of tolcapone on laboratory bar consumption. Adverse event (AE) reporting was low, with no significant difference in frequency or severity of AEs on tolcapone versus placebo. CONCLUSIONS: These data demonstrate that COMT inhibitors such as tolcapone may be useful therapeutics for AUD. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT02740582.

Enhancing prolonged exposure therapy for PTSD among veterans with oxytocin: Design of a multisite randomized controlled trial.

Posttraumatic stress disorder (PTSD) is the most highly prevalent mental health disorder among U.S. military Veterans. Prolonged Exposure (PE) therapy is one of the most widely used evidence-based treatments for PTSD, but there is substantial room for improvement in outcomes and retention rates. Accumulating data suggest that oxytocin offers a promising pharmacological approach towards achieving this goal. Therefore, the primary objective of this two-site Phase II study is to examine the ability of oxytocin (vs. placebo) administration combined with PE therapy to (1) reduce PTSD symptom severity, (2) accelerate the rate of PTSD symptom improvement, and (3) improve PE adherence and retention rates. To accomplish these objectives, we will employ a randomized, double-blind, placebo-controlled trial and use standardized, repeated dependent measures of change at five time points (baseline, mid-treatment, end of treatment, and 3 and 6 month follow-up). Intranasal oxytocin (40 IU) will be administered directly prior to each PE therapy session. Findings from this study will provide critical new information regarding the efficacy of oxytocin to augment psychosocial treatment for PTSD, as well as information regarding the physiological mechanisms underlying PTSD and positive treatment response. ClinicalTrials.gov Identifier: NCT04228289.

Restoration of functional sperm production in irradiated pubertal rhesus monkeys by spermatogonial stem cell transplantation.

BACKGROUND: In male pre-pubertal cancer patients, radiation and chemotherapy impact future fertility by eradication of spermatogonial stem cells (SSCs). In macaques, spermatogenesis could be regenerated by intratesticular transplantation of SSCs, but only a small percentage of spermatozoa produced were of donor origin. Transient hormone suppression with a GnRH antagonist (GnRH-ant) enhanced spermatogenic recovery from transplanted SSCs. OBJECTIVES: To evaluate donor-derived and endogenous spermatogenic recovery after SSC transplantation into irradiated monkeys and to test whether hormone suppression around the time of transplantation facilitates spermatogenic recovery. MATERIALS AND METHODS: Testes of 15 adult rhesus monkeys were irradiated with 7 Gy and 4 months later transplanted, to one of the testes, with cryopreserved testicular cells containing SSCs from unrelated monkeys. Monkeys were either treated with GnRH-ant for 8 weeks before transplantation, GnRH-ant from 4 weeks before to 4 weeks after transplantation, or with no GnRH-ant. Tissues were harvested 10 months after transplantation. RESULTS: Two of the 15 monkeys, a control and a pre-transplantation GnRH-ant-treated, showed substantially higher levels of testicular spermatogenesis and epididymal sperm output in the transplanted side as compared to the untransplanted. Over 84% of epididymal spermatozoa on the transplanted side had the donor genotype and were capable of fertilizing eggs after intracytoplasmic sperm injection forming morulae of the donor paternal origin. Low levels of donor spermatozoa (~1%) were also identified in the epididymis of three additional monkeys. Transplantation also appeared to enhance endogenous spermatogenesis. DISCUSSION AND CONCLUSION: We confirmed that SSC transplantation can be used for restoration of fertility in male cancer survivors exposed to irradiation as a therapeutic agent. The success rate of this procedure, however, is low. The success of filling the tubules with the cell suspension, but not the GnRH-ant treatment, was related to the level of colonization by transplanted cells.

Augmenting Treatment for Posttraumatic Stress Disorder and Co-Occurring Conditions with Oxytocin.

PURPOSE OF REVIEW: The goal of this manuscript is to review the extant literature examining the neurobiological and behavioral mechanisms underlying the potential utility of intranasal oxytocin as a novel pharmacologic intervention for the treatment of posttraumatic stress disorder (PTSD), and for the treatment of co-morbid PTSD and alcohol and substance use disorders. RECENT FINDINGS: Research indicates that intranasal oxytocin is a low-cost and easily accessible medication with an excellent safety profile. Oxytocin holds promise for facilitating more effective PTSD treatment, particularly when used in combination with evidence-supported psychotherapy interventions. There is still a significant need to identify the mechanisms of action underlying oxytocin treatment of PTSD, and to maximize methods of nasal spray delivery, examine dose-response outcomes, and clarify the characteristics of individuals and populations that are most likely to benefit from adjunctive oxytocin treatment. SUMMARY: Collectively, preclinical and human laboratory research suggest that oxytocin may be an effective mechanism by which treatment outcomes for PTSD and common comorbidities can be enhanced. Adequately powered randomized controlled trials are needed to address efficacy, identify predictors of treatment outcome, and to assess the use of intranasal oxytocin within appropriate PTSD populations.

Comparison of dynamic contrast-enhanced magnetic resonance imaging and contrast-enhanced ultrasound for evaluation of the effects of sorafenib in a rat model of hepatocellular carcinoma.

OBJECTIVES: To compare the accuracy of contrast-enhanced ultrasound (CEUS) and Dynamic contrast-enhanced (DCE) magnetic resonance imaging (MRI) for the assessment of changes in tissue vascularization as result of sorafenib treatment in a rat model of hepatocellular carcinoma (HCC). METHODS: Male Buffalo rats with orthotopic liver tumors treated daily with 7.5 mg/kg sorafenib via oral gavage for 2 weeks (n = 9) were subject to DCE-MRI and CEUS 2 weeks after tumor implantation - right before treatment initiation - and also after treatment completion - right before tumor harvest. Untreated animals (n = 10) were used as control. Tumor tissue sections were stained for hematoxylin-eosin, pimonidazole, and CD34 for quantitative assessment of necrosis, hypoxia, and microvessel density (MVD), respectively. RESULTS: Of all the DCE-MRI parameters that were evaluated, only volume transfer constant (Ktrans) measurements were significantly lower in sorafenib-treated tumors (0.18 vs 0.33 min-1, p < 0.01), indicating a substantial decrease in vascular permeability caused by the therapy. This reduction was associated with decreased MVD (3.9 vs 10.8% CD34+ cells, p < 0.01), higher tumor necrosis (31.9 vs 21.8%, p < 0.001) and hypoxia (19.7 vs 10.5% pimonidazole binding, p < 0.01). Moreover, statistical analysis demonstrate significant correlation of DCE-MRI Ktrans with histopathologic tissue necrosis (r = -0.537, p < 0.05) and MVD (r = 0.599, p < 0.05). Interestingly, none of the CEUS measurements were significantly different between the control and treatment groups, and did not show statistical correlation with any of the histopathological parameters assessed (p > 0.05). CONCLUSIONS: Sorafenib-induced reduction in vascular permeability in this preclinical model of HCC is detected more accurately through DCE-MRI than CEUS, and DCE-MRI parameters strongly correlate with histopathological changes in tissue vascularization and tissue necrosis.

Differentiation of primate primordial germ cell-like cells following transplantation into the adult gonadal niche.

A major challenge in stem cell differentiation is the availability of bioassays to prove cell types generated in vitro are equivalent to cells in vivo. In the mouse, differentiation of primordial germ cell-like cells (PGCLCs) from pluripotent cells was validated by transplantation, leading to the generation of spermatogenesis and to the birth of offspring. Here we report the use of xenotransplantation (monkey to mouse) and homologous transplantation (monkey to monkey) to validate our in vitro protocol for differentiating male rhesus (r) macaque PGCLCs (rPGCLCs) from induced pluripotent stem cells (riPSCs). Specifically, transplantation of aggregates containing rPGCLCs into mouse and nonhuman primate testicles overcomes a major bottleneck in rPGCLC differentiation. These findings suggest that immature rPGCLCs once transplanted into an adult gonadal niche commit to differentiate towards late rPGCs that initiate epigenetic reprogramming but do not complete the conversion into ENO2-positive spermatogonia.