Exploring chronic and transient tumor hypoxia for predicting the efficacy of hypoxia-activated pro-drugs.

Hypoxia, a low level of oxygen in the tissue, arises due to an imbalance between the vascular oxygen supply and oxygen demand by the surrounding cells. Typically, hypoxia is viewed as a negative marker of patients' survival, because of its implication in the development of aggressive tumors and tumor resistance. Several drugs that specifically target the hypoxic cells have been developed, providing an opportunity for exploiting hypoxia to improve cancer treatment. Here, we consider combinations of hypoxia-activated pro-drugs (HAPs) and two compounds that transiently increase intratumoral hypoxia: a vasodilator and a metabolic sensitizer. To effectively design treatment protocols with multiple compounds we used mathematical micro-pharmacology modeling and determined treatment schedules that take advantage of heterogeneous and dynamically changing oxygenation in tumor tissue. Our model was based on data from murine pancreatic cancers treated with evofosfamide (as a HAP) and either hydralazine (as a vasodilator), or pyruvate (as a metabolic sensitizer). Subsequently, this model was used to identify optimal schedules for different treatment combinations. Our simulations showed that schedules of HAPs with the vasodilator had a bimodal distribution, while HAPs with the sensitizer showed an elongated plateau. All schedules were more successful than HAP monotherapy. The three-compound combination had three local optima, depending on the HAPs clearance from the tissue interstitium, each two-fold more effective than baseline HAP treatment. Our study indicates that the three-compound therapy administered in the defined order will improve cancer response and that designing complex schedules could benefit from the use of mathematical modeling.

Investigation into the vascular contributors to dementia and the associated treatments.

As the average lifespan has increased, memory disorders have become a more pressing public health concern. However, dementia in the elderly population is often neglected in light of other health priorities. Therefore, expanding the knowledge surrounding the pathology of dementia will allow more informed decision-making regarding treatment within elderly and older adult populations. An important emerging avenue in dementia research is understanding the vascular contributors to dementia. This review summarizes potential causes of vascular cognitive impairment like stroke, microinfarction, hypertension, atherosclerosis, blood-brain-barrier dysfunction, and cerebral amyloid angiopathy. Also, this review address treatments that target these vascular impairments that also show promising results in reducing patient's risk for and experience of dementia.

Dichorionic-Diamniotic Twin Pregnancy in a Bicornuate Uterus With Twin A Affected by Ebstein's Anomaly.

Congenital Mullerian anomalies are rare developmental defects that result in malformation of the fallopian tubes, uterus, cervix, and vagina. The bicornuate uterus is one of the many variants of Mullerian anomalies, defined as having an external fundal indentation of greater than one centimeter. Pelvic ultrasound has a sensitivity of 99% for identifying bicornuate uteruses and is the predominant imaging device used for diagnosis. The cervical and uterine cavity anatomy in patients with a bicornuate uterus varies. The effect of maternal uterine structure on offspring development has been poorly documented. This report details a rare case of dichorionic-diamniotic twin pregnancy in a bicornuate uterus with one fetus affected by Ebstein's anomaly. Twin A was diagnosed by first-trimester ultrasound with right renal agenesis and Ebstein's anomaly. Twin B did not have any anatomical defects identified on ultrasound. Both twins were delivered via emergency repeat cesarean section at 34 weeks and four days due to nonreassuring fetal heart tracings and twin A in the breech presentation. Twin A and twin B were found to be in separate horns within the uterus during low transverse cesarean section. Twin A required endotracheal intubation in the delivery room due to respiratory distress. Both twins required neonatal intensive care treatment. Twin A was found to have a right pelvic kidney, rather than right renal agenesis, while in the neonatal intensive care unit. Females with germline mutations in the Mullerian duct and urogenital sinus development have resulted in concomitant malformations in the uterus and kidneys. This is a rare case of an infant with a cardiac anomaly born to a mother with a germline mutation. The relationship between congenital heart defects and uterine anomalies has not been identified. As seen in this case, maternal malformations impacting fetal cardiac development can be sporadic or result from germline mutations in mesoderm that have not been reported yet.

Children with Congenital Central Hypoventilation Syndrome Do Not Wake up to Ventilator Alarms.

PURPOSE: Congenital Central Hypoventilation Syndrome (CCHS) requires lifelong ventilatory support during sleep. Subjects with CCHS are vulnerable to sleep disturbances associated with treatments, monitoring alarms, and care they receive. We hypothesized that sleep would be disrupted in patients  with CCHS due to ventilatory support and other treatments at night. METHODS: An anonymous survey of patients with CCHS, age up to 17 years was conducted through REDCAP. Subjects were recruited in person, by flyer, email, and social media. Data collected included demographics, PHOX2B genotype, ventilatory support, treatments, nursing, and sleep parameters. RESULTS: We received 23 responses (35% female, 8.1 years ± 5.6). PHOX2B genotypes were 20/24 PARM (2), 20/25 PARM (4), 20/26 PARM (2), 20/27 PARM (9), ≥ 20/28 PARM (2), and NPARM (2). Two subjects did not indicate the PHOX2B genotype. 13/23 were ventilated by PPV via tracheostomy, 7 by NIPPV, 2 by diaphragm pacing, and 1 did not indicate. Additional treatments received at night included suctioning (9), aerosol (1), G-tube feeding (2), and none (11). Only 9 received nursing at night. 13 used pulse oximetry for monitoring, and 9 used both pulse oximetry and end tidal CO2 monitor. 17/23 rarely woke up due to ventilator or monitor alarms. 11/23 usually or sometimes woke up at least once a night; only 2/11 woke up due to alarms. 5/17 who rarely woke up to the alarms had night nursing. CONCLUSION: Most subjects with CCHS did not awaken to ventilator or monitoring alarms and a majority of these patients did not have nighttime nursing. (Mathur et al. in Sleep 43(Supplement_1):A333, 2020).

Nociceptor neurons promote IgE class switch in B cells.

Nociceptors, the high-threshold primary sensory neurons that trigger pain, interact with immune cells in the periphery to modulate innate immune responses. Whether they also participate in adaptive and humoral immunity is, however, not known. In this study, we probed if nociceptors have a role in distinct airway and skin models of allergic inflammation. In both models, the genetic ablation and pharmacological silencing of nociceptors substantially reduced inflammatory cell infiltration to the affected tissue. Moreover, we also found a profound and specific deficit in IgE production in these models of allergic inflammation. Mechanistically, we discovered that the nociceptor-released neuropeptide substance P helped trigger the formation of antibody-secreting cells and their release of IgE. Our findings suggest that nociceptors, in addition to their contributions to innate immunity, play a key role in modulating the adaptive immune response, particularly B cell antibody class switching to IgE.

Relation of urinary endothelin-1 to stress-induced pressure natriuresis in healthy adolescents.

We hypothesize that delayed natriuresis during mental stress increases the risk of hypertension and other diseases. Our preclinical studies demonstrate an important role for renal endothelin-1 (ET-1) in regulating sodium excretion. Thus, we predict ET-1 may be linked to the delayed stress response in at-risk individuals. We hypothesize that reduced renal ET-1 accounts for derangements in sodium handling under stress, a link never explored in a large human cohort. We determined urinary ET-1 excretion in three observational studies of changes in sodium excretion during mental stress, in which 776 healthy youth (15-19 years) enrolled in a 5-hour protocol (2 hours of rest before and after 1 hour of mental stress). In all studies, 60-minute urine samples were obtained throughout the protocol. Subjects were grouped as retainers (reduced sodium excretion during stress relative to baseline) or excreters (increased sodium excretion during stress relative to baseline). In excreters, ET-1 excretion was significantly increased from baseline to stress (+0.02 pg/min; P < .001). In contrast, ET-1 excretion was significantly higher (P = .028) in retainers than excreters at baseline but significantly reduced in retainers under stress (-0.02 pg/min; P < .001). ET-1 excretion declined further in retainers during recovery but returned to prestress levels in excreters. Albumin excretion and albumin-to-creatinine ratio were significantly higher in retainers (P = .022, P < .001, respectively). Thus, loss of ET-1-dependent natriuresis may account for sodium retention during stress and may predispose retainers to renal diseases such as hypertension and kidney disease.

Developing a novel test to detect cancer genes from microarray data.

DNA microarray technology can simultaneously screen thousands of gene expression profiles, transforming how genetics is applied in medicine. However, the lack of normality in microarray data renders common statistical methods ineffective. We propose a novel statistical method which does not require stringent assumptions but is still more powerful than some of its competitors. Using both simulation studies and clinical data, we show that our novel method outperforms previous methods. The limiting distribution for the proposed test is obtained for under null and alternative hypotheses. The proposed test will help make cancer treatment and gene therapy more successful, and it may facilitate research regarding cancer vaccinations. The proposed test may also help in the development of a prediction model in genetic profiling studies built on a subset of differentially expressed genes and the clinical data to assess the accuracy of the clinical prediction.