Wibergrosendal5617

Reproductive genetic carrier screening (RGCS) may be offered to all individuals and couples, regardless of family history or ethnicity. "Mackenzie's Mission" (MM) is an Australian RGCS pilot study, evaluating the offer of couple-based screening for ~1300 genes associated with around 750 autosomal and X-linked recessive childhood-onset conditions. Each member of the couple makes an individual decision about RGCS and provides consent. We developed a decision aid (RGCS-DA) to support informed decision-making in MM, suitable for couples who were either non-pregnant or in early pregnancy. A Delphi approach invited experts to review values statements related to various concepts of RGCS. Three review rounds were completed, seeking consensus for relevance and clarity of statements, incorporating recommended modifications in subsequent iterations. The final RGCS-DA contains 14 statements that achieved Delphi consensus plus the attitude scale of the measure of informed choice. This was then evaluated in cognitive talk aloud interviews with potential users to assess face and content validity. Minimal wording changes were required at this stage. After this process, the RGCS-DA was piloted with 15 couples participating in MM who were then interviewed about their decision-making. The RGCS-DA prompted discussion within couples and facilitated in depth consideration of screening. There was reassurance when values aligned and a sense of shared decision-making within the couple. This RGCS-DA may become a very useful tool in supporting couples' decision making and contribute to RGCS being feasible for scaled-up implementation.

Patients with bilateral lacrimal gland disease are a unique subset of patients where there is a paucity of literature. This presentation often represents systemic disease or malignancy and can cause diagnostic difficulties. We aim to describe the diagnoses and features of bilateral lacrimal gland disease.

Retrospective multi-centre case series involving 115 patients with bilateral lacrimal gland disease from 1995 to 2020.

115 patients were included. Their ages ranged from 9 to 85 (mean 47.3 years) with a female predominance (73, 63.5%). The most common category of diagnosis was inflammatory (69, 60%) followed by lymphoproliferative (23, 20%), structural (17, 14.8%) and other conditions (6, 5.2%). The five most common specific diagnoses were IgG4 related disease (20, 17.4%) and idiopathic orbital inflammatory disease (20, 17.4%), lymphoma (16, 13.9%), lacrimal gland prolapse (13, 11.3%), and sarcoidosis (11, 9.6%). Corticosteroid treatment was used most commonly (29, 25.2%) followed by observation (25, 2 presenting with bilateral lacrimal gland disease.

To assess the normal healing process of limbal-conjunctival autograft (LCA) after pterygium removal during the early postoperative period using anterior segment optical coherence tomography angiography (OCTA).

Prospective case series of seven patients undergoing pterygium removal with LCA transplantation procedure, imaged with anterior segment OCTA, and anterior segment colour photos prior to the procedure and on postoperative day (POD) 1, 3, 7 and 30. Revascularization of the graft was analysed quantitatively and qualitatively to estimate patterns of blood vessel growth. Association between revascularization to graft thickness was also investigated.

On POD 1, all autografts showed either minimal flow signal or no signal at all (Mean 7.1 ± 3.3%). Regrowth of blood vessels into the graft was detected on OCTA scans on POD3 (8.7 ± 3.6%) to 7 (14.3 ± 4.1%), as nonorganised vessels formation in their appearance. Blood vessels were seen growing in a centrifugal pattern towards the surrounding conjunctiva, originating from the underlying episcleral vessels. Revascularization flow signal was seen throughout nearly all graft extent on day 30 (21.6 ± 2.2%). Graft oedema was evident on the first week (Mean 611 ± 120 μm, 695 ± 84 μm, 639 ± 96 μm of POD 1, 3 and 7, respectively), reducing substantially by day 30 (300 ± 108 μm).

OCTA imaging can be used to assess the LCA healing process during the early postoperative period. Revascularization occurring as early as 3-7 days post-surgery, seems to originate from the underlying episcleral vessels. Therefore, careful handling of the bare scleral surface during surgery may be prudent for achieving an adequate healing process.

OCTA imaging can be used to assess the LCA healing process during the early postoperative period. Revascularization occurring as early as 3-7 days post-surgery, seems to originate from the underlying episcleral vessels. Therefore, careful handling of the bare scleral surface during surgery may be prudent for achieving an adequate healing process.

To analyse the entity of retinal vasculitis, including frosted branch angiitis (FBA), or retina vascular occlusion in patients with familial Mediterranean fever (FMF).

Retrospective collaborative case series using invitation by email to uveitis specialists around the Mediterranean basin. This series was combined with a literature review. Exclusion criteria included infectious diseases, Behçet's disease or other autoimmune diseases.

A total of 16 patients (21 eyes) had FMF and retinal vasculitis (FBA 11 patients, mild retinal vasculitis 5 patients). The mean age at onset of vasculitis was 29.5 ± 13.4 (range 9-62) with a female to male ratio of 9 to 7. In 19 eyes treated with various forms of corticosteroid and/or immunosuppression, the mean initial spectacle-corrected visual acuity improved from 6/194 to 6/10.5 at the last mean follow-up of 29.0 ± 34.9 months (p < 0.001). The most common FEVR mutations were M680I and M694V. In addition, retinal vascular occlusions included one case of central retinal artery occlusion and one case of branch retinal artery occlusion.

FBA and milder forms of retinal vasculitis are associated with FMF. Therapy involves an increase in colchicine dosage in early cases, a long period of oral corticosteroid, intravitreal dexamethasone implant or periocular corticosteroid in select cases, and combination therapy with systemic immunosuppression in severe cases. FMF needs to be included in the differential diagnosis of retinal vasculitis.

FBA and milder forms of retinal vasculitis are associated with FMF. Therapy involves an increase in colchicine dosage in early cases, a long period of oral corticosteroid, intravitreal dexamethasone implant or periocular corticosteroid in select cases, and combination therapy with systemic immunosuppression in severe cases. FMF needs to be included in the differential diagnosis of retinal vasculitis.The Hippo pathway is frequently dysregulated in cancer, leading to the unrestrained activity of its downstream targets, YAP/TAZ, and aberrant tumor growth. However, the precise mechanisms leading to YAP/TAZ activation in most cancers is still poorly understood. Analysis of large tissue collections revealed YAP activation in most head and neck squamous cell carcinoma (HNSCC), but only 29.8% of HNSCC cases present genetic alterations in the FAT1 tumor suppressor gene that may underlie persistent YAP signaling. EGFR is overexpressed in HNSCC and many other cancers, but whether EGFR controls YAP activation is still poorly understood. Here, we discover that EGFR activates YAP/TAZ in HNSCC cells, but independently of its typical signaling targets, including PI3K. Mechanistically, we find that EGFR promotes the phosphorylation of MOB1, a core Hippo pathway component, and the inactivation of LATS1/2 independently of MST1/2. Transcriptomic analysis reveals that erlotinib, a clinical EGFR inhibitor, inactivates YAP/TAZ. Remarkably, loss of LATS1/2, resulting in aberrant YAP/TAZ activity, confers erlotinib resistance on HNSCC and lung cancer cells. Our findings suggest that EGFR-YAP/TAZ signaling plays a growth-promoting role in cancers harboring EGFR alterations, and that inhibition of YAP/TAZ in combination with EGFR might be beneficial to prevent treatment resistance and cancer recurrence.A variety of mammals suppress reproduction when they experience poor physical condition or environmental harshness. In many marine mammal species, reproductive impairment has been correlated to polychlorinated biphenyls (PCBs), the most frequently measured chemical pollutants, while the relative importance of other factors remains understudied. We investigate whether reproductively active females abandon investment in their foetus when conditions are poor, exemplified using an extensively studied cetacean species; the harbour porpoise (Phocoena phocoena). Data on disease, fat and muscle mass and diet obtained from necropsies in The Netherlands were used as proxies of health and nutritional status and related to pregnancy and foetal growth. This was combined with published life history parameters for 16 other areas to correlate to parameters reflecting environmental condition mean energy density of prey constituting diets (MEDD), cumulative human impact and PCB contamination. Maternal nutritional status had significant effects on foetal size and females in poor health had lower probabilities of being pregnant and generally did not sustain pregnancy throughout gestation. Pregnancy rates across the Northern Hemisphere were best explained by MEDD. We demonstrate the importance of having undisturbed access to prey with high energy densities in determining reproductive success and ultimately population size for small cetaceans.Next generation modified antisense oligonucleotides (ASOs) are commercially approved new therapeutic modalities, yet poor productive uptake and endosomal entrapment in tumour cells limit their broad application. Here we compare intracellular traffic of anti KRAS antisense oligonucleotide (AZD4785) in tumour cell lines PC9 and LK2, with good and poor productive uptake, respectively. We find that the majority of AZD4785 is rapidly delivered to CD63+late endosomes (LE) in both cell lines. Importantly, lysobisphosphatidic acid (LBPA) that triggers ASO LE escape is presented in CD63+LE in PC9 but not in LK2 cells. Moreover, both cell lines recycle AZD4785 in extracellular vesicles (EVs); however, AZD4785 quantification by advanced mass spectrometry and proteomic analysis reveals that LK2 recycles more AZD4785 and RNA-binding proteins. Finally, stimulating LBPA intracellular production or blocking EV recycling enhances AZD4785 activity in LK2 but not in PC9 cells thus offering a possible strategy to enhance ASO potency in tumour cells with poor productive uptake of ASOs.Nasopharyngeal carcinoma (NPC) demonstrates significant regional differences and a high incidence in Southeast Asia and Southern China. Bactericidal/permeability-increasing-fold- containing family B member 1 (BPIFB1) is a relatively specific and highly expressed protein in the nasopharyngeal epithelium. BPIFB1 expression is substantially downregulated in NPC and is significantly associated with poor prognosis in patients with NPC. However, the specific molecular mechanism by which BPIFB1 regulates NPC is not well understood. In this study, we found that BPIFB1 inhibits vasculogenic mimicry by regulating the metabolic reprogramming of NPC. BPIFB1 decreases GLUT1 transcription by downregulating the JNK/AP1 signaling pathway. SSE15206 Altered glycolysis reduces the acetylation level of histone and decreases the expression of vasculogenic mimicry-related genes, VEGFA, VE-cadherin, and MMP2, ultimately leading to the inhibition of vasculogenic mimicry. To our knowledge, this is the first report on the role and specific mechanism of BPIFB1 as a tumor suppressor gene involved in regulating glycolysis and vasculogenic mimicry in NPC.