Dillonpuggaard8191

Hypoxia is a hallmark of solid tumors that promotes cell growth, survival, and metastasis and confers resistance to chemo and radiotherapies. Hypoxic responses are largely mediated by the transcription factors hypoxia-inducible factor 1α (HIF-1α) and HIF-2α. Our work demonstrates that HIF-2α is essential for colorectal cancer (CRC) progression. However, targeting hypoxic cells is difficult, and tumors rapidly acquire resistance to inhibitors of HIF-2α. To overcome this limitation, we performed a small molecule screen to identify HIF-2α-dependent vulnerabilities. Several known ferroptosis activators and dimethyl fumarate (DMF), a cell-permeable mitochondrial metabolite derivative, led to selective synthetic lethality in HIF-2α-expressing tumor enteroids. Our work demonstrated that HIF-2α integrated 2 independent forms of cell death via regulation of cellular iron and oxidation. First, activation of HIF-2α upregulated lipid and iron regulatory genes in CRC cells and colon tumors in mice and led to a ferroptosis-susceptible cell state. Second, via an iron-dependent, lipid peroxidation-independent pathway, HIF-2α activation potentiated ROS via irreversible cysteine oxidation and enhanced cell death. Inhibition or knockdown of HIF-2α decreased ROS and resistance to oxidative cell death in vitro and in vivo. Our results demonstrated a mechanistic vulnerability in cancer cells that were dependent on HIF-2α that can be leveraged for CRC treatment.Disrupting transmission of Borrelia burgdorferi sensu lato complex (B. burgdorferi) from infected ticks to humans is one strategy to prevent the significant morbidity from Lyme disease. We have previously shown that an anti-OspA human mAb, 2217, prevents transmission of B. burgdorferi from infected ticks in animal models. Selleckchem SSR128129E Maintenance of a protective plasma concentration of a human mAb for tick season presents a significant challenge for a preexposure prophylaxis strategy. Here, we describe the optimization of mAb 2217 by amino acid substitutions (2217LS M428L and N434S) in the Fc domain. The LS mutation led to a 2-fold increase in half-life in cynomolgus monkeys. In a rhesus macaque model, 2217LS protected animals from tick transmission of spirochetes at a dose of 3 mg/kg. Crystallographic analysis of Fab in complex with OspA revealed that 2217 bound an epitope that was highly conserved among the B. burgdorferi, B. garinii, and B. afzelii species. Unlike most vaccines that may require boosters to achieve protection, our work supports the development of 2217LS as an effective preexposure prophylaxis in Lyme-endemic regions, with a single dose at the beginning of tick season offering immediate protection that remains for the duration of exposure risk.Myelofibrosis (MF) is a non-BCR-ABL myeloproliferative neoplasm associated with poor outcomes. Current treatment has little effect on the natural history of the disease. MF results from complex interactions between (a) the malignant clone, (b) an inflammatory context, and (c) remodeling of the bone marrow (BM) microenvironment. Each of these points is a potential target of PPARγ activation. Here, we demonstrated the therapeutic potential of PPARγ agonists in resolving MF in 3 mouse models. We showed that PPARγ agonists reduce myeloproliferation, modulate inflammation, and protect the BM stroma in vitro and ex vivo. Activation of PPARγ constitutes a relevant therapeutic target in MF, and our data support the possibility of using PPARγ agonists in clinical practice.

Female childhood cancer survivors (CCS) are at risk of several late effects, such as metabolic syndrome (MetS) and premature ovarian insufficiency (POI). The objective is to study if POI is associated with risk of MetS and increased cardiovascular risk in CSS.

A cross-sectional study with a median time since the cancer diagnosis of 25 (12-41) years. Patients and controls were recruited from the South Medical Region of Sweden.

The study included 167 female CCS, median age 34 (19-57) years, diagnosed with childhood cancer at median age 8.4 (0.1-17.9) years together with 164 controls, matched for age, sex, ethnicity, residence, and smoking habits. All subjects were examined with fasting glucose, insulin, HbA1c, and lipid profile. Fat mass was calculated with dual-energy X-ray absorptiometry (DXA), and questionnaires for medication were obtained. Detailed information of cancer treatment was available.

POI was present in 13% (22/167) among CCS (hypothalamic/pituitary cause excluded) and in none among controls. MetS was present in 14% (24/167) among all CCS (P = 0.001), in 23% (5/22) of those with POI (P < 0.001), compared with 4% (6/164) among controls. OR for MetS in all CCS compared with controls was 4.4 (95% CI 1.8, 11.1) (P = 0.002) and among CCS with POI the OR was 7.7 (CI 2.1, 28.1) (P = 0.002).

The prevalence of MetS was higher in females treated for childhood cancer compared with controls, and the presence of POI significantly increased the risk of developing MetS.

The prevalence of MetS was higher in females treated for childhood cancer compared with controls, and the presence of POI significantly increased the risk of developing MetS.

We aimed to examine prospective associations between circulating fatty acids in early pregnancy and incident gestational diabetes mellitus (GDM) among Chinese pregnant women.

Analyses were based on two prospective nested case-control studies conducted in western China (336 GDM cases and 672 matched controls) and central China (305 cases and 305 matched controls). Fasting plasma fatty acids in early pregnancy (gestational age at enrollment 10.4 weeks(s.d., 2.0)) and 13.2 weeks (1.0), respectively) were determined by gas chromatography-mass spectrometry, and GDM was diagnosed based on the International Association of Diabetes in Pregnancy Study Groups criteria during 24-28 weeks of gestation. Multiple metabolic biomarkers (HOMA-IR (homeostatic model assessment for insulin resistance), HbA1c, c-peptide, high-sensitivity C-reactive protein, adiponectin, leptin, and blood lipids) were additionally measured among 672 non-GDM controls at enrollment.

Higher levels of saturated fatty acids (SFAs) 140 (pooled odds ratio, 1.41 for each 1-s.d. increase; 95% CI 1.25, 1.59) and 160 (1.19; 1.05, 1.35) were associated with higher odds of GDM. Higher levels of n-6 polyunsaturated fatty acid (PUFA) 182n-6 were strongly associated with lower odds of GDM (0.69; 0.60, 0.80). In non-GDM pregnant women, higher SFAs 140 and 160 but lower n-6 PUFA 182n-6 were generally correlated with unfavorable metabolic profiles.

We documented adverse associations of 140 and 160 but a protective association of 182n-6 with GDM among Chinese pregnant women. Our findings highlight the distinct roles of specific fatty acids in the onset of GDM.

We documented adverse associations of 140 and 160 but a protective association of 182n-6 with GDM among Chinese pregnant women. Our findings highlight the distinct roles of specific fatty acids in the onset of GDM.

Large birth size programs an elevated risk of type 2 diabetes in adulthood, but data are absent concerning glucose metabolic health impact in infancy. We sought to determine whether the large birth size is associated with insulin resistance and β-cell function in infancy and evaluate the determinants.

In the Canadian 3D birth cohort, we conducted a nested matched (12) study of 70 large-for-gestational-age (LGA, birth weight >90th percentile) and 140 optimal-for-gestational-age (OGA, 25th-75th percentiles) control infants. The primary outcomes were homeostasis model assessment of insulin resistance (HOMA-IR) and beta-cell function (HOMA-β) at age 2-years.

HOMA-IR and HOMA-β were similar in LGA and OGA infants. Adjusting for maternal and infant characteristics, decelerated growth in length during early infancy (0-3 months) was associated with a 25.8% decrease (95% confidence intervals 6.7-41.0%) in HOMA-β. During mid-infancy (3-12 months), accelerated growth in weight was associated with a 25.5% (0.35-56.9%) increase in HOMA-IR, in length with a 69.3% increase (31.4-118.0%) in HOMA-IR and a 24.5% (0.52-54.3%) increase in HOMA-β. Decelerated growth in length during late infancy (1-2 years) was associated with a 28.4% (9.5-43.4%) decrease in HOMA-IR and a 21.2% (3.9-35.4%) decrease in HOMA-β. Female sex was associated with higher HOMA-β, Caucasian ethnicity with lower HOMA-IR, and maternal smoking with lower HOMA-β.

This study is the first to demonstrate that large birth size is not associated with insulin resistance and β-cell function in infancy but infancy growth pattern matters. Decelerated infancy growth may be detrimental to beta-cell function.

This study is the first to demonstrate that large birth size is not associated with insulin resistance and β-cell function in infancy but infancy growth pattern matters. Decelerated infancy growth may be detrimental to beta-cell function.

Prolactinomas frequently cause amenorrhoea, galactorrhoea and infertility and require dopamine agonist (DA) treatment to normalize prolactin levels and hence, restore ovulation. The vast majority of female patients harbour microprolactinomas in whom DA treatment is usually discontinued at the time of pregnancy diagnosis and surveillance is generally limited as the symptomatic growth is considered very rare.

We report five cases of women harbouring a microprolactinoma in whom symptomatic pituitary apoplexy occurred during pregnancy. Only one necessitated surgery during pregnancy, while the others were treated conservatively by reintroducing DAs in three. A systematic literature review found reports of four additional cases among 20 cases of prolactinomas (both macro- and micro-prolactinomas) complicated by apoplexy during pregnancy.

During pregnancy, pituitary apoplexy may occur in pre-existing microprolactinomas, causing tumour enlargement and headache, which may be self-limiting but may require intervention by re-initation of dopamine agonists or surgery. Our literature review confirms that this clinical event is rare; nevertheless, physicians managing pregnant patients with microprolactinomas must be aware that symptomatic pituitary apoplexy may incidentally occur in all trimesters of pregnancy and require prompt radiological, endocrine and ophthalmological assessment and treatment.

During pregnancy, pituitary apoplexy may occur in pre-existing microprolactinomas, causing tumour enlargement and headache, which may be self-limiting but may require intervention by re-initation of dopamine agonists or surgery. Our literature review confirms that this clinical event is rare; nevertheless, physicians managing pregnant patients with microprolactinomas must be aware that symptomatic pituitary apoplexy may incidentally occur in all trimesters of pregnancy and require prompt radiological, endocrine and ophthalmological assessment and treatment.

Reports of retroperitoneal infection related to a sacral pressure injury (PI) are rare, and none of the reports described the direct spread of infection through the sacrum to the retroperitoneum. The authors present, to their knowledge, the first report of a severely infected PI that showed full-thickness sacral destruction and direct retroperitoneal penetration.

A 63-year-old female was referred for management of a stage 4 sacral PI complicated by a retroperitoneal abscess. The patient's comorbidities were diabetes mellitus and pemphigus foliaceus with steroid therapy-induced immunosuppression. Upon admission, the patient presented with a sacral PI producing copious purulent discharge that measured 5 cm × 3 cm. Magnetic resonance imaging revealed full-thickness sacral bone destruction and a massive retroperitoneal abscess, suggesting the sacral PI directly penetrated to the retroperitoneal space. Antibiotics were administered, and surgical debridement and sequestrectomy were performed. Negative pressure wound therapy (NPWT) with continuous saline irrigation was initiated.