Citations

Prader-Willi syndrome (PWS) is a developmental disorder caused by loss of maternally imprinted genes on 15q11-q13, including melanoma antigen gene family member L2 ( MAGEL2 ). The clinical phenotypes of PWS suggest impaired hypothalamic neuroendocrine function; however, the exact cellular defects are unknown. Here, we report deficits in secretory granule (SG) abundance and bioactive neuropeptide production upon loss of MAGEL2 in humans and mice. Unbiased proteomic analysis of Magel2 p Δ /m+ mice revealed a reduction in components of SG in the hypothalamus that was confirmed in 2 PWS patient–derived neuronal cell models. Mechanistically, we show that proper endosomal trafficking by the MAGEL2-regulated WASH complex is required to prevent aberrant lysosomal degradation of SG proteins and reduction of mature SG abundance. Importantly, loss of MAGEL2 in mice, NGN2-induced neurons, and human patients led to reduced neuropeptide production. Thus, MAGEL2 plays an important role in hypothalamic neuroendocrine function, and cellular defects in this pathway may contribute to PWS disease etiology. Moreover, these findings suggest unanticipated approaches for therapeutic intervention.

Background: Little is known about the detailed growth of the sphenoidal and temporal bones, even though they contribute significantly to the cranial base and cranial fossa skeletons. They also serve to connect the cranial vault with facial structure. This study details their morphologic development in isolated bicoronal synostosis and associated syndromes. Methods: Eighty-one CT scans were included (nonsyndromic bicoronal synostosis, n = 28; Apert syndrome associated with bicoronal synostosis, n = 19; Crouzon syndrome associated with bicoronal synostosis, n = 8; and controls, n = 26), and measured using Materialize software. Results: Sphenoidal and temporal bone volumes in nonsyndromic bicoronal synostosis are reduced 23% (P = 0.005) and 24%(P = 0.003) at 6 months of age, compared to controls. Apert and Crouzon syndrome patients developed similar reduced volumes. The greater wing of the sphenoid and pterygoid processes in nonsyndromic bicoronal synostosis are initially inferiorly rotated at 2 months of age, by 9.60° (P = 0.002) and 4.33° (P = 0.023), respectively. In Apert syndrome, these rotations were reduced by 4.82° (P = 0.003) and 12.60° (P < 0.001), (like Crouzon syndrome). However, in Apert syndrome, the length of pterygoid processes is shortened by 11% (P = 0.018) compared to nonsyndromic bicoronal synostosis. Crouzon syndrome skulls did not develop a statistically significant shortening relative to nonsyndromic bicoronal synostosis. Mediolateral expansion of the sphenoid in nonsyndromic bicoronal synostosis was less than normal (P = 0.023), and it was further reduced in syndromic skulls. Conclusion: Isolated bicoronal synostosis tends to reduce the volume of sphenoidal and temporal bones, and inferior and posterior rotation of the entire sphenoid. Syndromic conditions restrict sphenoidal rotation, and limit the expansion of sphenoidal greater wing and pterygoid plate.

Background: The association of isolated craniosynostosis and the influence of syndromic forms confound the understanding of craniofacial morphologic development. This study attempts to clarify the individual influences of isolated bicoronal synostosis, Apert syndrome, and Crouzon syndromes on skull base morphology. Methods:: One hundred seventeen computed tomographic scans were included (nonsyndromic bicoronal synostosis, n = 36; Apert syndrome with bicoronal synostosis, n = 25; Crouzon syndrome with bicoronal synostosis, n = 11; controls, n = 45). Cephalometric measurements were analyzed using Materialise software. Results: Nonsyndromic bicoronal synostosis patients developed a shortened cranial base length, with a significantly shortened distance between nasion and sella (p = 0.005). The cranial base angles of nonsyndromic bicoronal synostosis in both the cranial side (N-S-BA) and facial side (N-SO-BA) increased significantly, by 17.04 degrees (p < 0.001) and 11.75 degrees (p < 0.001), respectively. However, both the N-S-BA and N-SO-BA angles of Apert syndrome and Crouzon syndrome were narrowed more than that of nonsyndromic bicoronal synostosis [by 12.11 degrees (p < 0.001) and 12.44 degrees (p < 0.001), respectively, in Apert syndrome; and by 11.66 degrees (p = 0.007) and 13.71 degrees (p = 0.007), respectively, in Crouzon syndrome]. However, there is no statistically significant difference of these two angles between Apert syndrome and Crouzon syndrome, when they were only associated with bicoronal synostosis. Contrary to the relatively normal subcranial space of nonsyndromic bicoronal synostosis, both Apert and Crouzon syndromes developed a reduced subcranial space. Conclusions: Isolated bicoronal synostosis resulted in a flattened cranial base, whereas Apert syndrome and Crouzon syndrome developed a normal cranial base angle when only associated with bicoronal synostosis. The syndromic skulls had additional significantly reduced subcranial space.

AbstractThe etiology of triple-negative breast cancers (TNBC) is poorly understood. As many TNBCs develop prior to the initiation of breast cancer screening or at younger ages when the sensitivity of mammography is comparatively low, understanding the etiology of TNBCs is critical for discovering novel prevention approaches for these tumors. Furthermore, the higher incidence rate of estrogen receptor–negative breast cancers, and specifically, of TNBCs, among young African American women (AAW) versus white women is a source of racial disparities in breast cancer mortality. Whereas immune responses to TNBCs have received considerable attention in relation to prognosis and treatment, the concept that dysregulated immune responses may predispose to the development of TNBCs has received limited attention. We present evidence that dysregulated immune responses are critical in the pathogenesis of TNBCs, based on the molecular biology of the cancers and the mechanisms proposed to mediate TNBC risk factors. Furthermore, proposed risk factors for TNBC, especially childbearing without breastfeeding, high parity, and obesity, are more prevalent among AAW than white women. Limited data suggest genetic differences in immune responses by race, which favor a stronger Thr type 2 (Th2) immune response among AAW than white women. Th2 responses contribute to wound-healing processes, which are implicated in the pathogenesis of TNBCs. Accordingly, we review data on the link between immune responses and TNBC risk and consider whether the prevalence of risk factors that result in dysregulated immunity is higher among AAW than white women.

Abstract Over one million women in the United States receive biopsy diagnoses of benign breast disease (BBD) each year, which confer a 1.5–4.0-fold increase in breast cancer risk. Studies in the general population suggest that nonsteroidal anti-inflammatory agents (NSAID) lower breast cancer risk; however, associations among women with BBD are unknown. We assessed whether NSAID use among women diagnosed with BBD is associated with lower breast cancer risk. Participants included 3,080 women (mean age = 50.3 ± 13.5 years) in the Mayo BBD surgical biopsy cohort diagnosed between January 1, 1992 and December 31, 2001 who completed breast cancer risk factor questionnaires that assessed NSAID use, and whose biopsies underwent detailed pathology review, masked to outcome. Women were followed from date of BBD biopsy to breast cancer diagnosis (main outcome) or censoring (death, prophylactic mastectomy, reduction mammoplasty, lobular carcinoma in situ or last contact). Median follow-up time was 16.4 ± 6.0 years. Incident breast cancer was diagnosed among 312 women over a median follow-up of 9.9 years. Regular non-aspirin NSAID use was associated with lower breast cancer risk [HR = 0.63; 95% confidence interval (CI) = 0.46–0.85; P = 0.002] with trends of lower risk (highest tertiles of use vs. nonuse) for greater number of years used [HR = 0.55; 95% CI = 0.31–0.97; Ptrend = 0.003), days used per month (HR = 0.51; 95% CI = 0.33–0.80; Ptrend = 0.001) and lifetime number of doses taken (HR = 0.53; 95% CI = 0.31–0.89; Ptrend = 0.003). We conclude that nonaspirin NSAID use is associated with statistically significant lower breast cancer risk after a BBD biopsy, including a dose–response effect, suggesting a potential role for NSAIDs in breast cancer prevention among patients with BBD.

Background: Racial disparity in pathological consequences in skull growth may impact the treatment plan for different patient populations. This study attempts to explore the differences between Asian and Caucasian cranial morphology in Crouzon syndrome. Method: Ninety-one computed tomographic scans were included (Asian Crouzon syndrome, n = 12; Asian controls, n = 22; Caucasian Crouzon syndrome, n = 16; Caucasian controls, n = 41), and measured using Mimics and 3-matics software. Results: The entire cranial base length was reduced 11.92 mm (P = 0.004) in Asian Crouzon patients, and 14.58 mm (P < 0.001) in Caucasian Crouzon patients, compared to respective controls. The cranial base angle on the facial side of basicranium was more narrowed in Crouzon syndrome in both races, with similar changes of degrees (9.61°, P = 0.002, in Asian Crouzon; 9.20°, P = 0.019, in Caucasian Crouzon). However, the intracranial side was statistically more narrowed only in the Asian group (9.86°, P = 0.003). Both Asian and Caucasian Crouzon patients developed reduced posterior fossa volume, by 15% (P = 0.034) and 17% (P = 0.004), respectively. However, Caucasian Crouzon patients developed a more shortened anterior and middle cranial base, than that of Asian patients. The separation of lateral pterygoids was only significantly increased in Caucasian patients (5.49°, P < 0.001). Conclusion: Crouzon syndrome causes a shortened, widened, and kyphotic cranial base across both races. It also restricts the development of the posterior cranial fossa. However, the skull malformation is not the same between populations: Asian Crouzon patients developed more narrowed cranial base angulation on the intracranial side of basicranium, while Caucasian Crouzon patients developed more widened lateral pterygoids.

Cardiometabolic complications such as the metabolic syndrome and Type 2 Diabetes Mellitus (T2DM) are major causes of global morbidity and mortality. As sugar-sweetened beverages (SSBs) are implicated in this process, this study aimed to obtain greater mechanistic insights. Male Wistar rats (~200 g) were gavaged with a local SSB every day for a period of six months while the control group was gavaged with an iso-volumetric amount of water. Experimental dosages were calculated according to the surface area-to-volume ratio and were equivalent to 125 mL/day (in human terms). A proteomic analysis was performed on isolated liver samples and thereafter, markers of endoplasmic reticulum (ER) stress, antioxidant/oxidant capacity, calcium regulation, and mitochondrial functionality were assessed. These data show that SSB consumption resulted in (a) the induction of mild hepatic ER stress; (b) altered hepatic mitochondrial dynamics; and (c) perturbed calcium handling across mitochondria-associated ER membranes. Despite significant changes in markers of ER stress, the antioxidant response and calcium handling (proteomics data), the liver is able to initiate adaptive responses to counteract such stressors. However, the mitochondrial data showed increased fission and decreased fusion that may put the organism at risk for developing insulin resistance and T2DM in the longer term.

Abstract Advances in treatment of oligodendroglioma represent arguably the most significant recent development in the treatment of brain tumors, with multiple clinical trials demonstrating that median survival is approximately doubled in patients with World Health Organization grade II and III 1p/19q codeleted gliomas (ie, oligodendrogliomas) treated with procarbazine, lomustine, vincristine chemotherapy and radiation vs radiation alone. However, chemoradiotherapy itself is not without morbidity, including both short-term toxicities primarily related to chemotherapy and longer-term cognitive issues likely due to radiation. Patients and physicians both desire maximally effective therapy with minimal toxicity, and it remains unclear whether some patients with macroscopic residual disease after surgery can safely delay therapy, to avoid or delay toxicity, while simultaneously preserving the full benefits of treatment. In this article, experts in the field discuss the rationale for the approaches of up-front treatment with chemoradiotherapy and initial observation, respectively.