Endometriosis Typology and Ovarian Cancer Risk.

Importance: Endometriosis has been associated with an increased risk of ovarian cancer; however, the associations between endometriosis subtypes and ovarian cancer histotypes have not been well-described. Objective: To evaluate the associations of endometriosis subtypes with incidence of ovarian cancer, both overall and by histotype. Design, Setting, and Participants: Population-based cohort study using data from the Utah Population Database. The cohort was assembled by matching 78 893 women with endometriosis in a 1:5 ratio to women without endometriosis. Exposures: Endometriosis cases were identified via electronic health records and categorized as superficial endometriosis, ovarian endometriomas, deep infiltrating endometriosis, or other. Main Outcomes and Measures: Estimated adjusted hazard ratios (aHRs), adjusted risk differences (aRDs) per 10 000 women, and 95% CIs for overall ovarian cancer, type I ovarian cancer, and type II ovarian cancer comparing women with each type of endometriosis with women without endometriosis. Models accounted for sociodemographic factors, reproductive history, and past gynecologic operations. Results: In this Utah-based cohort, the mean (SD) age at first endometriosis diagnosis was 36 (10) years. There were 597 women with ovarian cancer. Ovarian cancer risk was higher among women with endometriosis compared with women without endometriosis (aHR, 4.20 [95% CI, 3.59-4.91]; aRD, 9.90 [95% CI, 7.22-12.57]), and risk of type I ovarian cancer was especially high (aHR, 7.48 [95% CI, 5.80-9.65]; aRD, 7.53 [95% CI, 5.46-9.61]). Ovarian cancer risk was highest in women with deep infiltrating endometriosis and/or ovarian endometriomas for all ovarian cancers (aHR, 9.66 [95% CI, 7.77-12.00]; aRD, 26.71 [95% CI, 20.01-33.41]), type I ovarian cancer (aHR, 18.96 [95% CI, 13.78-26.08]; aRD, 19.57 [95% CI, 13.80-25.35]), and type II ovarian cancer (aHR, 3.72 [95% CI, 2.31-5.98]; aRD, 2.42 [95% CI, -0.01 to 4.85]). Conclusions and Relevance: Ovarian cancer risk was markedly increased among women with ovarian endometriomas and/or deep infiltrating endometriosis. This population may benefit from counseling regarding ovarian cancer risk and prevention and could be an important population for targeted screening and prevention studies.

Gaps in Parental Understanding of Sleep Disturbances During Maintenance Therapy for Pediatric Acute Lymphoblastic Leukemia.

Background: Acute lymphoblastic leukemia (ALL) is the most common cancer in childhood, with survival rates approaching 90%. Sleep disturbance is common among ALL patients, often developing during the initial stages of chemotherapy treatment. While there have been significant efforts to understand and intervene in this issue during survivorship, there is far less research on children who are actively receiving treatment. In the current study, we sought to better understand the parent's experience in the sleep domain during maintenance therapy, including their perceptions of how their child's medical team had managed sleep disturbances, and recommendations for how to improve sleep management. Method: Fifteen parents of pediatric ALL patients (aged 4-12 years) completed semistructured interviews. Interview content was analyzed using a multistage thematic analysis. Results: Parents consistently expressed feeling unprepared to manage the sleep disruptions that arose during treatment, often reporting that they did not recall being told this would be a side effect. They were enthusiastic about learning how to improve their child's sleep, though they did not want pharmacotherapeutic interventions or additional medical/psychosocial appointments to address this. Conclusion: Despite consistent provider communication on sleep, parents report limited knowledge of the issue. This provides an obvious intervention target to improve treatment-related sleep disturbances. Clear messaging may help direct parents' attention and expectations regarding their child's treatment and potential for disturbed sleep, possibly in the form of a behavioral intervention that empowers parents with information about how to support their child's sleep health while they are undergoing treatment for ALL.

Recurrence Risk of Fetal Growth Restriction: Management of Subsequent Pregnancies.

Fetal growth restriction (FGR) is a common obstetric complication that predisposes to mortality across the lifespan. Women with a prior pregnancy affected by FGR have a 20% to 30% risk of recurrence, but effective preventive strategies are lacking. Pharmacologic interventions to prevent FGR are lacking. Low-dose aspirin may be somewhat effective, but low-molecular-weight heparin and sildenafil are not. Surveillance in a subsequent pregnancy may consist of serial ultrasonography with timing and frequency determined by the clinical severity in the index pregnancy. Once FGR is diagnosed, the principal management strategy consists of close surveillance and carefully timed delivery.

Improving hindlimb locomotor function by Non-invasive AAV-mediated manipulations of propriospinal neurons in mice with complete spinal cord injury.

After complete spinal cord injuries (SCI), spinal segments below the lesion maintain inter-segmental communication via the intraspinal propriospinal network. However, it is unknown whether selective manipulation of these circuits can restore locomotor function in the absence of brain-derived inputs. By taking advantage of the compromised blood-spinal cord barrier following SCI, we optimized a set of procedures in which AAV9 vectors administered via the tail vein efficiently transduce neurons in lesion-adjacent spinal segments after a thoracic crush injury in adult mice. With this method, we used chemogenetic actuators to alter the excitability of propriospinal neurons in the thoracic cord of the adult mice with a complete thoracic crush injury. We showed that activating these thoracic neurons enables consistent and significant hindlimb stepping improvement, whereas direct manipulations of the neurons in the lumbar spinal cord led to muscle spasms without meaningful locomotion. Strikingly, manipulating either excitatory or inhibitory propriospinal neurons in the thoracic levels leads to distinct behavioural outcomes, with preferential effects on standing or stepping, two key elements of the locomotor function. These results demonstrate a strategy of engaging thoracic propriospinal neurons to improve hindlimb function and provide insights into optimizing neuromodulation-based strategies for treating SCI.

Recent advances with cyclin-dependent kinase inhibitors: therapeutic agents for breast cancer and their role in immuno-oncology.

Introduction: Collaborative interactions between several diverse biological processes govern the onset and progression of breast cancer. These processes include alterations in cellular metabolism, anti-tumor immune responses, DNA damage repair, proliferation, anti-apoptotic signals, autophagy, epithelial-mesenchymal transition, components of the non-coding genome or onco-mIRs, cancer stem cells and cellular invasiveness. The last two decades have revealed that each of these processes are also directly regulated by a component of the cell cycle apparatus, cyclin D1. Area covered: The current review is provided to update recent developments in the clinical application of cyclin/CDK inhibitors to breast cancer with a focus on the anti-tumor immune response. Expert opinion: The cyclin D1 gene encodes the regulatory subunit of a proline-directed serine-threonine kinase that phosphorylates several substrates. CDKs possess phosphorylation site selectivity, with the phosphate-acceptor residue preceding a proline. Several important proteins are substrates including all three retinoblastoma proteins, NRF1, GCN5, and FOXM1. Over 280 cyclin D3/CDK6 substrates have b\een identified. Given the diversity of substrates for cyclin/CDKs, and the altered thresholds for substrate phosphorylation that occurs during the cell cycle, it is exciting that small molecular inhibitors targeting cyclin D/CDK activity have encouraging results in specific tumors.

Point-of-Care Tissue Analysis Using Miniature Mass Spectrometer.

The combination of direct sampling ionization and miniature mass spectrometer presents a promising technical pathway of point-of-care analysis in clinical applications. In this work, a miniature mass spectrometry system was used for analysis of tissue samples. Direct tissue sampling coupled with extraction spray ionization was used with a home-built miniature mass spectrometer, Mini 12. Lipid species in tissue samples were well profiled in rat brain, kidney, and liver in a couple of minutes. By incorporating a photochemical (Paternò-Büchi) reaction, fast identification of lipid C═C location was realized. Relative quantitation of the lipid C═C isomer was performed by calculating the intensity ratio C═C diagnostic product ions, by which FA 18:1 (Δ9)/FA 18:1 (Δ11) was found to change significantly in mouse cancerous breast tissue samples. Accumulation of 2-hydroxylglutarate in human glioma samples, not in normal brains, can also be easily identified for rapid diagnosis.

Peripheral Neuropathy and Hindlimb Paralysis in a Mouse Model of Adipocyte-Specific Knockout of Lkb1.

Brown adipose tissues (BAT) burn lipids to generate heat through uncoupled respiration, thus representing a powerful target to counteract lipid accumulation and obesity. The tumor suppressor liver kinase b1 (Lkb1) is a key regulator of cellular energy metabolism; and adipocyte-specific knockout of Lkb1 (Ad-Lkb1 KO) leads to the expansion of BAT, improvements in systemic metabolism and resistance to obesity in young mice. Here we report the unexpected finding that the Ad-Lkb1 KO mice develop hindlimb paralysis at mid-age. Gene expression analyses indicate that Lkb1 KO upregulates the expression of inflammatory cytokines in interscapular BAT and epineurial brown adipocytes surrounding the sciatic nerve. This is followed by peripheral neuropathy characterized by infiltration of macrophages into the sciatic nerve, axon degeneration, reduced nerve conductance, and hindlimb paralysis. Mechanistically, Lkb1 KO reduces AMPK phosphorylation and amplifies mammalian target-of-rapamycin (mTOR)-dependent inflammatory signaling specifically in BAT but not WAT. Importantly, pharmacological or genetic inhibition of mTOR ameliorates inflammation and prevents paralysis. These results demonstrate that BAT inflammation is linked to peripheral neuropathy.

Comparison of interventions for pain control with tenaculum placement: a randomized clinical trial.

OBJECTIVE: Although previous studies have demonstrated that a variety of local anesthetics are effective to decrease pain associated with tenaculum placement, no studies directly compare an injection with a topical anesthetic. The objective of this study was therefore to compare mean pain scores with tenaculum placement after an intracervical lidocaine injection or topical lidocaine gel. STUDY DESIGN: A randomized, single-blinded trial of women presenting for office gynecologic procedures that required a tenaculum. Women aged 18 years or older were randomized to receive either a 1% lidocaine intracervical injection or topical application of 2% lidocaine gel to the cervix immediately prior to tenaculum placement. The primary outcome was pain at the time of tenaculum placement, measured on a 100 mm Visual Analog Scale. Secondary outcomes included pain with the intervention and satisfaction with tenaculum placement. RESULTS: Seventy-four women were enrolled and randomized; 35 subjects in each group met criteria for analysis. The two groups had similar socio-demographic characteristics. Women who received the injection had lower mean pain levels at tenaculum placement [12.3 mm (S.D. 17.4 mm) versus 36.6 mm (S.D. 23.0 mm), p<.001] but higher mean pain levels with study drug application [20.4 mm (S.D. 19.4 mm) versus 5.9 mm (S.D. 8.6 mm), p<.001]. Satisfaction with tenaculum placement was similar for the two groups. CONCLUSION: Mean pain with tenaculum placement is lower after receiving a lidocaine injection than after receiving a topical lidocaine gel. Satisfaction with tenaculum placement is similar with both interventions.