Effectiveness of Duloxetine on Oxaliplatin-induced Allodynia and Hyperalgesia in Rats.

Development of painful oxaliplatin-induced peripheral neuropathy (OIPN) is a major problem in people who receive oxaliplatin as part of cancer treatment. The pain experienced by those with OIPN can be seriously debilitating and lead to discontinuation of an otherwise successful treatment. Duloxetine is currently the only recommended treatment for established painful OIPN recommended by the American Society of Clinical Oncology, but its preventative ability is still not clear. This study examined the ability of duloxetine to prevent signs of chronic OIPN in female (n = 12) and male (n = 21) rats treated with the chemotherapeutic agent oxaliplatin. Using an established model of OIPN, rats were started on duloxetine (15 mg) one week prior to oxaliplatin administration and continued duloxetine for 32 days. Behavioral testing for mechanical allodynia and mechanical hyperalgesia was done with selected von Frey filaments. Significant posttreatment differences were found for allodynia in female (p = .004), but not male rats. Duloxetine was associated with significant differences for hyperalgesia in both female (p < .001) and male (p < .001) rats. These findings provide preliminary evidence of the preventative effects of duloxetine on both oxaliplatin-induced allodynia and hyperalgesia in male and female rats, with a difference noted in response between the sexes.

Variability of DNA Repair and Oxidative Stress Genes Associated with Worst Pain in Breast Cancer Survivors on Aromatase Inhibitors.

Pain is a problem affecting women with breast cancer (HR+BrCa) receiving aromatase inhibitor (AI) therapy. We investigated the relationship between single-nucleotide polymorphisms (SNPs) in DNA repair and oxidative stress genes and perceived worst pain after 6 months of AI therapy. We explored 39 SNPs in genes involved in DNA repair (ERCC2, ERCC3, ERCC5, and PARP1) and oxidative stress (CAT, GPX1, SEPP1, SOD1, and SOD2) in women with HR+BrCa receiving adjuvant therapy (AI ± chemotherapy; n = 138). Pain was assessed via the Brief Pain Inventory. Hurdle regression was used to evaluate the relationship between each associated allele and (1) the probability of pain and (2) the severity of worst pain. ERCC2rs50872 and ERCC5rs11069498 were associated with the probability of pain and had a significant genetic risk score (GRS) model (p = 0.003). ERCC2rs50872, ERCC5rs11069498, ERCC5rs4771436, ERCC5rs4150360, PARP1rs3219058, and SEPP1rs230819 were associated with the severity of worst pain, with a significant GRS model (conditional mean estimate = 0.45; 95% CI = 0.29, 0.60; p < 0.001). These results suggest DNA repair and oxidative stress pathways may play a role in the probability of pain and the severity of worst pain. As healthcare delivery moves towards the model of precision healthcare, nurses may, in the future, be able to use these results to tailor patient care based on GRS.

Sensory processing of native and non-native phonotactic patterns in the alpha and beta frequency bands.

The phonotactic patterns of one's native language are established within cortical network processing during development. Sensory processing of native language phonotactic patterns established in memory may be modulated by top-down signals within the alpha and beta frequency bands. To explore sensory processing of phonotactic patterns in the alpha and beta frequency bands, electroencephalograms (EEGs) were recorded from native Polish and native English-speaking adults as they listened to spoken nonwords within same and different nonword pairs. The nonwords contained three phonological sequence onsets that occur in the Polish and English languages (/pət/, /st/, /sət/) and one onset sequence /pt/, which occurs in Polish but not in English onsets. Source localization modeling was used to transform 64-channel EEGs into brain source-level channels. Spectral power values in the low frequencies (2-29 Hz) were analyzed in response to the first nonword in nonword pairs within the context of counterbalanced listening-task conditions, which were presented on separate testing days. For the with-task listening condition, participants performed a behavioral task to the second nonword in the pairs. For the without-task condition participants were only instructed to listen to the stimuli. Thus, in the with-task condition, the first nonword served as a cue for the second nonword, the target stimulus. The results revealed decreased spectral power in the beta frequency band for the with-task condition compared to the without-task condition in response to native language phonotactic patterns. In contrast, the task-related suppression effects in response to the non-native phonotactic pattern /pt/ for the English listeners extended into the alpha frequency band. These effects were localized to source channels in left auditory cortex, the left anterior temporal cortex and the occipital pole. This exploratory study revealed a pattern of results that, if replicated, suggests that native language speech perception is supported by modulations in the alpha and beta frequency bands.

PROTECTIVE EFFECTS OF HUMANIN-G IN HEMORRHAGIC SHOCK IN FEMALE MICE VIA AMPKα1-INDEPENDENT MECHANISMS.

ABSTRACT: Introduction: Despite therapeutic advances in hemorrhagic shock, mortality from multiple organ failure remains high. We previously showed that the α1 subunit of AMP-activated protein kinase (AMPK), a crucial regulator of mitochondrial function, exerts a protective role in hemorrhagic shock. Humanin is a mitochondrial peptide with cytoprotective properties against cellular stress. Here, we investigated whether AMPKα1 influences systemic levels of endogenous humanin in hemorrhagic shock and whether treatment with the synthetic analog humanin-G affords beneficial effects. Methods: AMPKα1 wild-type (WT) and knockout (KO) female mice were subjected to hemorrhagic shock followed by resuscitation with blood and lactated Ringer's solution. In short-term studies, mice were treated with humanin-G or vehicle and sacrificed at 3 h after resuscitation; in survival studies, mice were treated with PEGylated humanin-G and monitored for 7 days. Results: Compared with the vehicle WT group, KO mice exhibited severe hypotension, cardiac mitochondrial damage, and higher plasma levels of Th17 cytokines but had similar lung injury and similar plasma elevation of endogenous humanin. Treatment with humanin-G improved lung injury, mean arterial blood pressure, and survival in both WT and KO mice, without affecting systemic cytokine or humanin levels. Humanin-G also ameliorated cardiac mitochondrial damage and increased adenosine triphosphate levels in KO mice. Beneficial effects of humanin-G were associated with lung cytoplasmic and nuclear activation of the signal transducer and activator of transcription-3 (STAT3) in AMPKα1-independent manner with marginal or no effects on mitochondrial STAT3 and complex I subunit GRIM-19. Conclusions: Our data indicate that circulating levels of humanin increase during hemorrhagic shock in AMPKα1-independent fashion as a defense mechanism to counteract metabolic derangement and that administration of humanin-G affords beneficial effects through STAT3 activation even in the absence of a functional AMPKα1.

Long-term resistance to 5-fluorouracil promotes epithelial-mesenchymal transition, apoptosis evasion, autophagy, and reduced proliferation rate in colon cancer cells.

The drug, 5-fluorouracil (5FU) is a standard first-line treatment for colorectal cancer (CRC) patients. However, drug resistance acquisition remains an important challenge for effective clinical outcomes. Here, we established a long-term drug-resistant CRC model and explored the cellular events underlying 5FU resistance. We showed that 5FU-treated cells (HCT-116 5FUR) using a prolonged treatment protocol were significantly more resistant than parental cells. Likewise, cell viability and IC50 values were also observed to increase in HCT-116 5FUR cells when treated with increasing doses of oxaliplatin, indicating a cross-resistance mechanism to other cytotoxic agents. Moreover, HCT-116 5FUR cells exhibited metabolic and molecular changes, as evidenced by increased thymidylate synthase levels and upregulated mRNA levels of ABCB1. HCT-116 5FUR cells were able to overcome S phase arrest and evade apoptosis, as well as activate autophagy, as indicated by increased LC3B levels. Cells treated with low and high doses displayed epithelial-mesenchymal transition (EMT) features, as observed by decreased E-cadherin and claudin-3 levels, increased vimentin protein levels, and increased SLUG, ZEB2 and TWIST1 mRNA levels. Furthermore, HCT-116 5FUR cells displayed enhanced migration and invasion capabilities. Interestingly, we found that the 5FU drug-resistance gene signature is positively associated with the mesenchymal signature in CRC samples, and that ABCB1 and ZEB2 co-expressed at high levels could predict poor outcomes in CRC patients. Overall, the 5FU long-term drug-resistance model established here induced various cellular events, and highlighted the importance of further efforts to identify promising targets involved in more than one cellular event to successfully overcome drug-resistance.

The serine/threonine kinase MINK1 directly regulates the function of promigratory proteins.

Upregulation of the developmental Wnt planar cell polarity (Wnt/PCP) pathway is observed in many cancers and is associated with cancer development. We have recently shown that PRICKLE1, a core Wnt/PCP pathway component, is a marker of poor prognosis in triple-negative breast cancer (TNBC). PRICKLE1 is phosphorylated by the serine/threonine kinase MINK1 and contributes to TNBC cell motility and invasiveness. However, the identity of the substrates of MINK1 and the role of MINK1 enzymatic activity in this process remain to be addressed. We used a phosphoproteomic strategy to identify MINK1 substrates, including LL5ß (also known as PHLDB2). LL5ß anchors microtubules at the cell cortex through its association with CLASP proteins to trigger focal adhesion disassembly. LL5ß is phosphorylated by MINK1, promoting its interaction with CLASP proteins. Using a kinase inhibitor, we demonstrate that the enzymatic activity of MINK1 is involved in PRICKLE1-LL5ß complex assembly and localization, as well as in cell migration. Analysis of gene expression data reveals that the concomitant upregulation of levels of mRNA encoding PRICKLE1 and LL5ß, which are MINK1 substrates, is associated with poor metastasis-free survival in TNBC patients. Taken together, our results suggest that MINK1 may represent a potential target for treatment of TNBC.

Use of thromboelastography in children on extracorporeal membrane oxygenation.

INTRODUCTION: Extracorporeal membrane oxygenation (ECMO) profoundly impacts inflammatory and coagulation pathways, and strict monitoring is essential to guide therapeutic anticoagulation. Thromboelastography (TEG) offers a global evaluation of whole blood hemostatic system components and may be a valuable measurement of hemostatic function in these patients. There is a paucity of data correlating TEG parameters with standard measures of coagulation in heparinized pediatric patients. METHODS: Children on ECMO during a 10-year period were retrospectively reviewed. Standard measures of coagulation were matched to TEGs drawn within 30 min of each other. RESULTS: Out of 296 unique patients with 331 ECMO runs, 74.3% (n = 246) had at least one set of matched laboratory samples for a total of 2502 matched samples. The aPTT correlated with R-time (p<0.001). Platelets and fibrinogen correlated with α-angle (p<0.001). Fibrinogen (p<0.001) and platelets (p<0.001) were each associated with maximum amplitude (MA). 158 (47.7%) patients had at least one bleeding complication, and 100 (30.2%) had at least one thrombotic complication. Interestingly, a decreasing MA was associated with increased thrombotic complications (p<0.001). DISCUSSION: TEG correlated well with traditional measures of hemostasis in pediatric ECMO patients. However, there was not a clear benefit of the TEG over these other measures LEVEL OF EVIDENCE: III.

Acoustic-level and language-specific processing of native and non-native phonological sequence onsets in the low gamma and theta-frequency bands.

Acoustic structures associated with native-language phonological sequences are enhanced within auditory pathways for perception, although the underlying mechanisms are not well understood. To elucidate processes that facilitate perception, time-frequency (T-F) analyses of EEGs obtained from native speakers of English and Polish were conducted. Participants listened to same and different nonword pairs within counterbalanced attend and passive conditions. Nonwords contained the onsets /pt/, /pət/, /st/, and /sət/ that occur in both the Polish and English languages with the exception of /pt/, which never occurs in the English language in word onset. Measures of spectral power and inter-trial phase locking (ITPL) in the low gamma (LG) and theta-frequency bands were analyzed from two bilateral, auditory source-level channels, created through source localization modeling. Results revealed significantly larger spectral power in LG for the English listeners to the unfamiliar /pt/ onsets from the right hemisphere at early cortical stages, during the passive condition. Further, ITPL values revealed distinctive responses in high and low-theta to acoustic characteristics of the onsets, which were modulated by language exposure. These findings, language-specific processing in LG and acoustic-level and language-specific processing in theta, support the view that multi scale temporal processing in the LG and theta-frequency bands facilitates speech perception.

Effect of intraoperative fluid type on postoperative systemic inflammatory response and end organ dysfunction following total pancreatectomy with islet autotransplantation in children.

PURPOSE: To evaluate the effect of intraoperative fluid type [half normal saline (0.45NS) or lactated Ringer's solution (LR)] on the risk of systemic inflammatory response syndrome (SIRS) and acute kidney injury after total pancreatectomy with islet autotransplantation in children. METHODS: Retrospective review where demographics, operative details, systemic inflammatory response, and evaluation for end organ dysfunction over the first 5 postoperative days was obtained. Mixed effects Poisson regression compared risk of SIRS and acute kidney injury by intraoperative fluid type. RESULTS: Forty three patients were included with no difference in demographic characteristics between groups. SIRS was observed in 95, 77, and 71% over post operative days 1, 3, and 5. Intraoperative fluid type was found to not be associated with postoperative SIRS (RR: 0.91, p = 0.23). However, female sex (RR: 1.30, p < 0.01), increased BMI (RR: 1.08, p < 0.01), and longer operative time (RR: 1.07, p < 0.01) were found to be factors that are associated with increased risk of postoperative SIRS. Intraoperative 0.45NS use was associated with increased acute kidney injury compared to LR on postoperative day 1 (52% vs 0%, p < 0.01), but not on postoperative days 3 or 5. CONCLUSION: Intraoperative fluid type (0.45NS vs LR) does not increase the risk of postoperative SIRS in children after TPIAT. Predictive factors that are associated with an increased risk of eliciting postoperative SIRS includes female sex, increased BMI, and longer operative times. LEVEL OF EVIDENCE: III.

Identification of PDZ Interactions by Affinity Purification and Mass Spectrometry Analysis.

Identification of protein networks becomes indispensable for determining the function of a given protein of interest. Some proteins harbor a PDZ binding motif (PDZBM) located at the carboxy-terminus end. This motif is necessary to recruit PDZ domain proteins which are involved in signaling, trafficking, and maintenance of cell architecture. In the present chapter, we present two complementary approaches (immunopurification and peptide-based purification procedures) followed by mass spectrometry analysis to identify PDZ domain proteins associated to a given protein of interest. As proof of example, we focus our attention on TANC1 which is a scaffold protein harboring a PDZBM at its carboxy-terminus. Using these two approaches, we identified several PDZ domain containing proteins. Some of them were found with both approaches, and some were specifically identified using peptide-based purification procedure. This exemplifies advantages and differences of both strategies to identify PDZ interactions.

Language Learning Under Varied Conditions: Neural Indices of Speech Perception in Bilingual Turkish-German Children and in Monolingual Children With Developmental Language Disorder (DLD).

Lateral temporal measures of the auditory evoked potential (AEP) including the T-complex (positive Ta and negative Tb), as well as an earlier negative peak (Na) index maturation of auditory/speech processing. Previous studies have shown that these measures distinguish neural processing in children with typical language development (TD) from those with disorders and monolingual from bilingual children. In this study, bilingual children with Turkish as L1 and German as L2 were compared with monolingual German-speaking children with developmental language disorder (DLD) and monolingual German-speaking children with TD in order to disentangle effects of limited language input vs. reduced perceptual abilities in the processing of speech and non-speech stimuli. Sensory processing reflected by the T-complex (or from lateral temporal electrode sites) was compared in response to a German vowel and a sine-wave tone in the three groups of children, ages 5 through 6 years. Stimuli were presented while children watched a muted video. Auditory evoked potentials (AEPs) were time-locked to the vowels and tones. AEPs to the frequent (standard) stimuli within an oddball paradigm were analyzed at the left (T7) and right (T8) temporal electrode sites.The results revealed language status (monolingual, bilingual, and DLD), stimulus (vowel and tone), and language test measures (receptive and expressive) all influenced the T-complex amplitudes. Particularly, the peak amplitude of Ta was modulated by language status and stimulus type. Bilingual children had significantly more negative Ta responses than the monolingual children with TD for both vowels and tones while DLD children differed from TD children only for the vowel stimulus. The amplitude of the T-complex was overall more negative at the left than at the right site. The Na peak latency was longer for the bilingual group than that observed for the two monolingual groups. The Tb latency was shorter for DLD and bilingual groups than that for TD children in the vowel condition, but no such latency difference between DLD and bilingual children was found. We suggest that the attenuated T-complex for bilingual children indicates continued plasticity of the auditory cortex to allow for learning of novel, second-language speech sounds.

Symptom Science: Omics and Response to Non-Pharmacological Interventions.

Incorporating omics into non-pharmacological intervention research design could provide a better understanding of the variability in response to these interventions. It would also provide evidence for precision-based non-pharmacological interventions, including interventions focused on symptoms. The purpose of this manuscript was to present examples of studies that have used omics to examine response to non-pharmacological intervention. Using the interventions of exercise, diet (related to obesity), cognitive based therapy, and alternative mind-body practices (meditation, yoga, and tai chi), PubMed was searched to identify studies that incorporated genomic or other omic approaches as part of a non-pharmacological intervention. The review identified genes associated with the effectiveness of each of the interventions. Although there were no genes that were associated with all four interventions, there were nine genes that were the focus of more than one intervention (ACE, BDNF, COMT, CXCL8, IL6, SL6A4, TNF, GSTM1, PTGER3). All nine of these genes were either directly or indirectly biologically related to one another, suggesting that this cadre of genes could serve as an initiation point for investigations using omic approaches to better understand response to non-pharmacological interventions.

Risk profile of subcutaneous port placement in small children.

BACKGROUND/PURPOSE: Long-term central venous access is a safe and common procedure in children. However, complications with devices are a reality. Smaller children are thought to have a higher rate of complication after port placement, and some surgeons avoid placing ports with an arbitrary weight cutoff out of concern for surgical site morbidity. METHODS: We performed a multi-institutional retrospective review of 500 patients less than 5 years of age undergoing port placement at three large volume children's hospitals from 2014 to 2018. Patients were divided by weight greater than or less than 10 kg at the time of insertion. Statistical analysis was performed to evaluate for differences in outcomes between the two groups. RESULTS: The majority of ports were placed for chemotherapy access (71.8%). Other indications included long-term infusions (18.8%) and difficult chronic IV access (9.4%). Of the 500 charts reviewed, 110 (22%) experienced some documented complication (28.9% <10 kg, 20.6% >10 kg, p = 0.096). There were no differences between the two groups in terms of the type or timing of complications. Overall, 16.3% of ports required removal prior to the end of therapy owing to a complication. Complication rate per day with the port in place was not different between the two groups (<10 kg: 0.68 complications/1000 port-days vs >10 kg 0.44 complications/1000 port-days, p = 0.068). CONCLUSION: Weight less than 10 kg was not associated with a significantly higher incidence of any type of port complication in our cohort. This suggests that concern for complications should not exclude children less than 10 kg from port placement. TYPE OF STUDY: Multi-institutional retrospective review. LEVEL OF EVIDENCE: Level III.

Standardizing Preoperative Evaluation for Pediatric Central Venous Access: A Care Algorithm to Improve Safety.

Central vascular access device (CVAD) placement is a common procedure in children. When selecting a CVAD, available evidence and specified indications should be used to choose the device that best supports the patient's treatment and carries the lowest risks. A multidisciplinary team developed a care algorithm to standardize preoperative screening before pediatric CVAD placement, with 3 major parts: CVAD selection, patient risk stratification, and preoperative evaluation. Using a stepwise approach of provider education and incorporation into the electronic health record, the team achieved 82% stratification among inpatients. The team's algorithm integrates the existing literature and recommendations for safe and effective CVAD placement.

Hepatic Pseudoaneurysm Incidence After Liver Trauma.

BACKGROUND: Posttraumatic hepatic artery pseudoaneurysm is a potentially devastating complication after complex liver injury. Increasing computed tomography (CT) use may lead to more frequent identification of posttraumatic hepatic complications. This study was designed to determine the rate of hepatic pseudoaneurysm after traumatic liver injury. METHODS: We conducted a retrospective review of patients at an urban level 1 trauma center over 5 y (2012-2016). Injury characteristics, patient management, and complications were extracted from trauma registry data and chart review. RESULTS: Six hundred thirty-four hepatic injuries (11 no grade/no CT, 159 grade I, 154 grade II, 165 grade III, 93 grade IV, and 52 grade V) were identified from our trauma registry. No patient with a grade I or II injury had a subsequent bleeding complication. Eighteen patients had a documented hepatic pseudoaneurysm: grade III n = 3 (1.8%), grade IV n = 6 (6.5%), grade V n = 9 (17.3%). The median time to pseudoaneurysm identification was 6.5 d. Seven pseudoaneurysms were found on asymptomatic surveillance CT-angiography on average 5 d after injury. Eleven patients were symptomatic at the time of CT-angiography performed at a median of 9 d after admission. Of the 11 symptomatic patients, four were in hemorrhagic shock, and two died from hepatic-related complications. CONCLUSIONS: The incidence of hepatic artery pseudoaneurysm increases with higher grade liver injury. Aggressive surveillance for hepatic pseudoaneurysm with interval CT-angiography 5-7 d postinjury may be warranted, especially for grade IV and V injuries.

Characterizing Early Inpatient Death After Trauma.

BACKGROUND: There is a paucity of data to predict early death or futility after trauma. The objective of this study was to characterize the laboratory values, blood product administration, and hospital disposition for patients with trauma who died within 72 h of admission. METHODS: All deaths within 72 h of admission over a 5-y period at a level I trauma center were reviewed. Blood transfusion within the first 4 h of arrival and patient disposition from the emergency department to the operating room (OR), surgical intensive care unit, or the neuroscience intensive care unit (NSICU) were analyzed. Kaplan-Meier curves were generated to determine time to death. RESULTS: A total of 622 subjects were identified; 39.5% died in the emergency department, 10.6% went directly to the OR, 13.6% were admitted to the surgical intensive care unit, and 29.7% admitted to the NSICU. Of these subjects, 201 (32.2%) patients received blood within the first 4 h. By 24 h, early blood transfusion was associated with more rapid death for patients who were admitted to the NSICU (80% versus 60% mortality, P = 0.01) but not for patients taken directly to the OR (80% versus 70% mortality, P = 0.2). Admission coagulopathy by international normalized ratio (P < 0.01), but not anemia (P = 0.64) or acidosis (P = 0.45), correlated with a shorter time to death. In contrast, laboratory values obtained at 4 h after admission did not correlate with time to death. CONCLUSIONS: Our data demonstrate that admission coagulation derangement and need for early blood product transfusion are the two factors most associated with early death after injury, particularly in those patients with traumatic brain injury. These data will help construct future models for futility of continued care in patients with trauma.

Outcomes in the giant omphalocele population: A single center comprehensive experience.

BACKGROUND/PURPOSE: Morbidity and mortality in the giant omphalocele population is complicated by large abdominal wall defects, physiologic aberrancies, and congenital anomalies. We hypothesized different anomalies and treatment types would affect outcomes. METHODS: A 2009-2018 retrospective chart review of giant omphaloceles was performed. Exclusions included cloacal exstrophy, transfer after 3 weeks, surgery prior to transfer, conjoined twins, or not yet achieving fascial closure. Thirty-five patients met criteria and mortality and operative morbidity categorized them into favorable (n = 20) or unfavorable (n = 15) outcomes. Odds ratios analyzed potential predictors. Survivors were stratified into staged (n = 11), delayed (n = 8), and primary closure (n = 6) for subgroup analysis. RESULTS: Unfavorable outcomes were associated with other major congenital anomalies, sac rupture, and major cardiac anomalies, but had significantly lower odds with increasing gestational age (p = 0.03) and birth weight (p < 0.001). In survivors, the primary group was younger at repair (p < 0.001) and had shorter length of stay (hospital p = 0.02, neonatal intensive care unit p = 0.005). There was no significant difference for sepsis, ventilator days, return to the operating room, or ventral hernia. CONCLUSIONS: Predictions of overall outcomes in the giant omphalocele population require analysis of multiple variables. Our findings demonstrated increased odds of unfavorable outcomes in major cardiac anomalies, pulmonary hypertension, genetic diagnosis, other major anomalies, polyhydramnios, postnatal sac rupture, increasing omphalocele sac diameter, lower O/E TLV, lower gestational age at birth, lower birth weight, and repair other than primary. In those surviving to repair, surgical outcomes analyses demonstrated an earlier age of repair and a shorter length of stay for those patients able to be closed primarily; however further research is necessary to determine overall superiority between operative treatment types. LEVEL OF EVIDENCE: Level III.

The Influence of Physical Activity and Epigenomics On Cognitive Function and Brain Health in Breast Cancer.

The risk of breast cancer increases with age, with the majority of women diagnosed with breast cancer being postmenopausal. It has been estimated that 25-75% of women with breast cancer experience changes in cognitive function (CF) related to disease and treatment, which compromises psychological well-being, decision making, ability to perform daily activities, and adherence to cancer therapy. Unfortunately, the mechanisms that underlie neurocognitive changes in women with breast cancer remain poorly understood, which in turn limits the development of effective treatments and prevention strategies. Exercise has great potential as a non-pharmaceutical intervention to mitigate the decline in CF in women with breast cancer. Evidence suggests that DNA methylation, an epigenetic mechanism for gene regulation, impacts CF and brain health (BH), that exercise influences DNA methylation, and that exercise impacts CF and BH. Although investigating DNA methylation has the potential to uncover the biologic foundations for understanding neurocognitive changes within the context of breast cancer and its treatment as well as the ability to understand how exercise mitigates these changes, there is a dearth of research on this topic. The purpose of this review article is to compile the research in these areas and to recommend potential areas of opportunity for investigation.

Pain condition and sex differences in the descending noradrenergic system following lateral hypothalamic stimulation.

The lateral hypothalamus (LH) is known to modulate nociception via the descending noradrenergic system in acute nociception, but less is known about its role in neuropathic pain states. In naïve females, LH stimulation produces opposing effects of α-adrenoceptors, with α2-adrenoceptors mediating antinociception, while pronociceptive α1-adrenoceptors attenuate the effect. Whether this opposing response is seen in neuropathic conditions or in naïve males is unknown. We used a mixed factorial design to compare male and female rats with chronic constriction injury (CCI) to naïve rats, measured by Total Paw Withdrawal (TPW) responses to a thermal stimulus. Rats received one of three doses of carbachol to stimulate the LH followed by intrathecal injection of either an α1- or an α2-adrenoceptor antagonist (WB4101 or yohimbine, resp.) or saline for control. Overall, naïve rats showed a more pronounced opposing alpha-adrenergic response than CCI rats (p < 0.04). Naïve male and female rats demonstrated antinociception following α1-adrenoceptor blockade and hyperalgesia following α2-adrenoceptor blockade. Male CCI rats also showed dose dependent effects from either WB4101 or yohimbine (p < 0.05), while female CCI rats had significant antinociception from WB4101 (p < 0.05), but no effect from yohimbine. These results support the idea that peripheral nerve damage differentially alters the descending noradrenergic modulatory system in male and female rats, and notably, that female CCI rats do not show antinociception from descending noradrenergic input. These findings are suggestive that clinical therapies that recruit the descending noradrenergic system may require a different approach based on patient gender.

The Tumor Suppressor SCRIB is a Negative Modulator of the Wnt/ß-Catenin Signaling Pathway.

SCRIB is a scaffold protein containing leucine-rich repeats (LRR) and PSD-95/Dlg-A/ZO-1 domains (PDZ) that localizes at the basolateral membranes of polarized epithelial cells. Deregulation of its expression or localization leads to epithelial defects and tumorigenesis in part as a consequence of its repressive role on several signaling pathways including AKT, ERK, and HIPPO. In the present work, a proteomic approach is used to characterize the protein complexes associated to SCRIB and its paralogue LANO. Common and specific sets of proteins associated to SCRIB and LANO by MS are identified and an extensive landscape of their associated networks and the first comparative analysis of their respective interactomes are provided. Under proteasome inhibition, it is further found that SCRIB is associated to the ß-catenin destruction complex that is central in Wnt/ß-catenin signaling, a conserved pathway regulating embryonic development and cancer progression. It is shown that the SCRIB/ß-catenin interaction is potentiated upon Wnt3a stimulation and that SCRIB plays a repressing role on Wnt signaling. The data thus provide evidence for the importance of SCRIB in the regulation of the Wnt/ß-catenin pathway.