Brain activation associated with low- and high-intensity concentric versus eccentric isokinetic contractions of the biceps brachii: An fNIRS study.

Studies have shown that neural responses following concentric (CON) and eccentric (ECC) muscle contractions are different, which suggests differences in motor control associated with CON and ECC contractions. This study aims to determine brain activation of the left primary motor cortex (M1) and left and right dorsolateral prefrontal cortices (DLPFCs) during ECC and CON of the right bicep brachii (BB) muscle at low- and high-contraction intensities. Eighteen young adults (13M/5F, 21-35 years) were recruited to participate in one familiarization and two testing sessions in a randomized crossover design. During each testing session, participants performed either ECC or CON contractions of the BB (3 sets × 8 reps) at low- (25% of maximum ECC/CON, 45°/s) and high-intensity (75% of maximum ECC/CON, 45°/s) on an isokinetic dynamometer. Eleven-channel functional near-infrared spectroscopy was used to measure changes in oxyhemoglobin (O2 Hb) from the left M1, and left and right DLPFC during ECC and CON contractions. Maximum torque for ECC was higher than CON (43.3 ± 14.1 vs. 46.2 ± 15.7 N m, p = 0.025); however, no differences in O2 Hb were observed between contraction types at low or high intensities in measured brain regions. High-intensity ECC and CON contractions resulted in greater increases in O2 Hb of M1 and bilateral DLPFC compared to low-intensity ECC and CON contractions (p = 0.014). Our findings suggest no differences in O2 Hb responses between contraction types at high and low intensities. High-contraction intensities resulted in greater brain activation of the M1 and bilateral DLPFC, which may have implications for neurorehabilitation to increase central adaptations from exercise.

A blood-based multi-pathway biomarker assay for early detection and staging of Alzheimer's disease across ethnic groups.

INTRODUCTION: Existing blood-based biomarkers for Alzheimer's disease (AD) mainly focus on its pathological features. However, studies on blood-based biomarkers associated with other biological processes for a comprehensive evaluation of AD status are limited. METHODS: We developed a blood-based, multiplex biomarker assay for AD that measures the levels of 21 proteins involved in multiple biological pathways. We evaluated the assay's performance for classifying AD and indicating AD-related endophenotypes in three independent cohorts from Chinese or European-descent populations. RESULTS: The 21-protein assay accurately classified AD (area under the receiver operating characteristic curve [AUC] = 0.9407 to 0.9867) and mild cognitive impairment (MCI; AUC = 0.8434 to 0.8945) while also indicating brain amyloid pathology. Moreover, the assay simultaneously evaluated the changes of five biological processes in individuals and revealed the ethnic-specific dysregulations of biological processes upon AD progression. DISCUSSION: This study demonstrated the utility of a blood-based, multi-pathway biomarker assay for early screening and staging of AD, providing insights for patient stratification and precision medicine. HIGHLIGHTS: The authors developed a blood-based biomarker assay for Alzheimer's disease. The 21-protein assay classifies AD/MCI and indicates brain amyloid pathology. The 21-protein assay can simultaneously assess activities of five biological processes. Ethnic-specific dysregulations of biological processes in AD were revealed.

Genetic variants in the receptor for advanced glycation end products (RAGE) gene were associated with circulating soluble RAGE level but not with renal function among Asians with type 2 diabetes: a genome-wide association study.

BACKGROUND: The soluble receptor for advanced glycation end products (sRAGE) has been shown to play an important role in diabetic complications. We conducted genome-wide association study (GWAS) of sRAGE in Asian type 2 diabetes mellitus (T2DM) patient and validated the association in an independent cohort of T2DM. METHODS: GWAS for sRAGE was performed in 2058 T2DM patients. Associations between single-nucleotide polymorphisms (SNPs) and plasma sRAGE level were analyzed in an additive model using a linear mixed model. To validate the associations, we performed de novo genotyping in an independent cohort (n = 1984). We selected the top SNP for assessment with diabetic kidney disease (DKD). RESULTS: The strongest SNP, rs2070600C>T (P = 1.21 × 10-52), was a genotyped, missense SNP located on chromosome 6, corresponding to the RAGE (AGER) gene locus, the gene encoding RAGE. Conditioning analysis on rs2070600 revealed that rs2071288C>T was the top genotyped independent SNP (P = 8.36 × 10-10). Both SNPs were strongly and dose-dependently correlated with sRAGE level (TT = 399.6 pg/mL, CT = 737.0 pg/mL and CC = 967.0 pg/mL, P < 0.001 for rs2070600; TT = 687.9 pg/mL, CT = 737.6 pg/mL and CC = 904.7 pg/mL, P < 0.001 for rs2072188). Both SNPs were robustly replicated in the independent cohort, especially among Chinese patients (P = 9.02 × 10-72 for rs2070600; P = 1.13 × 10-9 for rs2071288). Log-transformed sRAGE was associated with DKD after adjustment for age, gender and ethnicity in pooled cohorts [odds ratio 2.536 (95% confidence interval 1.864-3.450), P < 0.001]. However, we did not observe any significant association between rs2070600 and DKD. CONCLUSIONS: Common variants in RAGE are strongly associated with plasma sRAGE level, which is associated with DKD. However, we did not find a causal link between sRAGE and renal function by Mendelian randomization.

Plasma proteomics of diabetic kidney disease among Asians with younger-onset type 2 diabetes.

CONTEXT: Patients with younger onset of type 2 diabetes (YT2D) have increased risk for kidney failure compared to those with late onset. However, the mechanism of diabetic kidney disease (DKD) progression in this high-risk group is poorly understood. OBJECTIVES: To identify novel biomarkers and potential causal proteins associated with DKD progression in patients with YT2D. DESIGN AND PARTICIPANTS: Among YT2D (T2D onset age ≤ 40 years), 144 DKD progressors (cases) were matched for T2D onset age, sex, and ethnicity with 292 non-progressors (controls) and divided into discovery and validation sets. DKD progression was defined as decline of estimated glomerular filtration rate (eGFR) of 3ml/min/1.73m2 or greater or 40% decline in eGFR from baseline. 1472 plasma proteins were measured through a multiplex immunoassay that uses a proximity extension assay technology. Multivariable logistic regression was used to identify proteins associated with DKD progression. Mendelian randomization (MR) was used to evaluate causal relationship between plasma proteins and DKD progression. RESULTS: 42 plasma proteins were associated with DKD progression, independent of traditional cardio-renal risk factors, baseline eGFR and urine albumin-to-creatinine ratio (uACR). The proteins identified were related to inflammatory and remodelling biological processes. Our findings suggested angiogenin as one of the top signals (odds ratio =5.29, 95% CI 2.39-11.73, P = 4.03 × 10-5). Furthermore, genetically determined plasma angiogenin level was associated with increased odds of DKD progression. CONCLUSION: Large-scale proteomic analysis identified novel proteomic biomarkers for DKD progression in YT2D. Genetic evidence suggest a causal role of plasma angiogenin in DKD progression.

Structural basis for the cooperative DNA recognition by Smad4 MH1 dimers.

Smad proteins form multimeric complexes consisting of the 'common partner' Smad4 and receptor regulated R-Smads on clustered DNA binding sites. Deciphering how pathway specific Smad complexes multimerize on DNA to regulate gene expression is critical for a better understanding of the cis-regulatory logic of TGF-ß and BMP signaling. To this end, we solved the crystal structure of the dimeric Smad4 MH1 domain bound to a palindromic Smad binding element. Surprisingly, the Smad4 MH1 forms a constitutive dimer on the SBE DNA without exhibiting any direct protein-protein interactions suggesting a DNA mediated indirect readout mechanism. However, the R-Smads Smad1, Smad2 and Smad3 homodimerize with substantially decreased efficiency despite pronounced structural similarities to Smad4. Therefore, intricate variations in the DNA structure induced by different Smads and/or variant energetic profiles likely contribute to their propensity to dimerize on DNA. Indeed, competitive binding assays revealed that the Smad4/R-Smad heterodimers predominate under equilibrium conditions while R-Smad homodimers are least favored. Together, we present the structural basis for DNA recognition by Smad4 and demonstrate that Smad4 constitutively homo- and heterodimerizes on DNA in contrast to its R-Smad partner proteins by a mechanism independent of direct protein contacts.

A Pair of Siblings With Wolfram Syndrome: A Review of the Literature and Treatment Options.

Wolfram syndrome (WS) is a rare genetic disorder typically characterized by juvenile onset diabetes mellitus, optic atrophy, hearing loss, diabetes insipidus, and neurodegeneration. There would be a high index of clinical suspicion for WS when clinical manifestations of type 1 diabetes and optic atrophy present together. Genetic analysis is often required to confirm the diagnosis. We describe a pair of Chinese siblings diagnosed with WS at ages 20 and 24 years, respectively. DNA sequencing of the WFS1 gene which encodes for Wolframin ER Transmembrane Glycoprotein identified a heterozygous nonsense variant NM_006005.3: c.1999C>T p.(Gln667*) and a heterozygous missense variant c.2170C>T p.(Pro724Ser) in exon 8 of the gene for both siblings. There is no curative treatment for WS and management of this debilitating disease is aimed at treating individual clinical manifestations, slowing disease progression, and improving quality of life. Treatment with liraglutide, a glucagon-like-peptide-1 receptor agonist, and tauroursodeoxycholic acid was started for the younger sibling, the proband. There was reduction in insulin requirements and improvement in glycemic control. The other sibling was not offered liraglutide due to her complex treatment regimen for end-organ failure. Genetic testing is a valuable tool to detect WS early to allow precise and prompt diagnosis, thereby facilitating the coordinated care from a multidisciplinary team of clinicians.

Sudden onset anhidrosis in an otherwise healthy male.

Acquired idiopathic generalised anhidrosis (AIGA) is a rare disorder that is characterised by sudden onset generalised absence of sweating without any dermatological, neurological or sweat gland abnormalities. AIGA predominately affects young males, mostly involving patients of Asian descent. There have been approximately 100 reported cases worldwide, most of which were reported in Japan. In Singapore, it is rarely seen with one case series on 15 cases of AIGA reported in a 2014 study. Here, we present a case of AIGA who responded well to conservative management with sweating activity.

Lesbian, gay, bisexual, transgender, queer and intersex (LGBTQI+) healthcare in Singapore: perspectives of non-governmental organisations and clinical year medical students.

PURPOSE: International studies document that lesbian, gay, bisexual, transgender, queer and intersex (LGBTQI+) patients face significant health disparities. Studies exploring the attitudes, knowledge, preparedness and comfort levels of healthcare students towards LGBTQI+ health have been conducted in the United States, United Kingdom and Malaysia. This study aims to investigate stigma in healthcare for LGBTQI+ patients in Singapore, and possible upstream factors within medical education. METHODS: This mixed-methods study adopts a convergent parallel design. The Health Stigma and Discrimination Framework was referenced to devise in-depth interviews with representatives from 13 LGBTQI-affirming non-governmental organisations, analysed through thematic analysis. 320 clinical medical students were surveyed about attitudes, knowledge, comfort, preparedness, and perceived importance of/towards LGBTQI+ health, analysed via descriptive statistics and multivariate regression. RESULTS: Prevailing stigma in Singaporean society against LGBTQI+ individuals is exacerbated in healthcare settings. Doctors were cited as unfamiliar or uncomfortable with LGBTQI+ health, possibly from lack of training. Among medical students surveyed, the median composite attitudes, comfort and preparedness index was 3.30 (Interquartile Range (IQR) = 0.50), 3.17 (IQR = 0.83), 2.50 (IQR = 1.00) respectively. Only 12.19% of students answered all 11 true-false questions about LGBTQI+ health correctly. CONCLUSION: Medical students in Singapore have scored sub-optimally in their knowledge and preparedness towards LGBTQI+ health, while interpersonal and structural stigma in healthcare towards LGBTQI+ people in Singapore negatively affects health and wellbeing. These findings are an impetus to improve medical training in this area. High scores among medical students in attitudes, comfort and perceived importance of LGBTQI+ topics demonstrate that there is space for LGBTQI+ health in the local medical education curriculum. Curricular interventions can prioritise content knowledge, communication skills and sensitivity.

Association between mental health, psychological characteristics, and motivational functions of volunteerism among Polish and Ukrainian volunteers during the Russo-Ukrainian War.

The Russo-Ukrainian War has led to a humanitarian crisis, and many people volunteered to help affected refugees. This cross-sectional survey study investigates the relationships between the psychological impact of participation, coping mechanisms, and motivational functions of volunteering during the Russo-Ukrainian War among 285 Ukrainian and 435 Polish volunteers (N = 720). Multivariate linear regression was used to examine relationships between motivational functions and psychosocial and demographic characteristics. Ukrainian volunteers reported significantly higher Hyperarousal and Avoidance, Depression, Anxiety, and Stress, Problem-focused, Emotion-focused, and Avoidant coping, as well as total scores of Hardiness and Psychological Capital than Polish counterparts. Linear regression analysis found that Impact of the Event Scale results, Coping with Stress, being a female, unemployed, and religious were significantly associated with higher motivational functions. Ukrainian volunteers could significantly reduce negative feelings and strengthen social networks and religious faith by volunteering, while Polish volunteers were significantly more likely to gain skills and psychosocial development from helping others.

Regulation of tumor angiogenesis by integrin-linked kinase (ILK).

We show that integrin-linked kinase (ILK) stimulates the expression of VEGF by stimulating HIF-1alpha protein expression in a PKB/Akt- and mTOR/FRAP-dependent manner. In human prostate cancer cells, knockdown of ILK expression with siRNA, or inhibition of ILK activity, results in significant inhibition of HIF-1alpha and VEGF expression. In endothelial cells, VEGF stimulates ILK activity, and inhibition of ILK expression or activity results in the inhibition of VEGF-mediated endothelial cell migration, capillary formation in vitro, and angiogenesis in vivo. Inhibition of ILK activity also inhibits prostate tumor angiogenesis and suppresses tumor growth. These data demonstrate an important and essential role of ILK in two key aspects of tumor angiogenesis: VEGF expression by tumor cells and VEGF-stimulated blood vessel formation.

Ethnic-Specific Type 2 Diabetes Risk Factor PAX4 R192H Is Associated with Attention-Specific Cognitive Impairment in Chinese with Type 2 Diabetes.

BACKGROUND: Type 2 diabetes mellitus (T2DM) has been shown to increase the risks of cognitive decline and dementia. Paired box gene 4 (PAX4), a transcription factor for beta cell development and function, has recently been implicated in pathways intersecting Alzheimer's disease and T2DM. OBJECTIVE: In this report, we evaluated the association of the ethnic-specific PAX4 R192H variant, a T2DM risk factor for East Asians which contributes to earlier diabetes onset, and cognitive function of Chinese T2DM patients. METHODS: 590 Chinese patients aged 45-86 from the SMART2D study were genotyped for PAX4 R192H variation using Illumina OmniExpress-24 Array. The Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) which had been validated in the Singapore population was administered to assess five cognitive domains: immediate memory, visuospatial/constructional, language, attention, and delayed memory. Multiple linear regression was used to assess the association of the R192H risk allele and cognitive domains. RESULTS: Patients with two PAX4 R192H risk alleles showed significantly lower attention index score (ß= -8.46, 95% CI [-13.71, -3.21], p = 0.002) than patients with wild-type alleles after adjusting for age, gender, diabetes onset age, HbA1c, body-mass index, renal function, lipid profiles, systolic blood pressure, metformin usage, smoking history, education level, Geriatric Depression Scale score, and presence of APOEɛ4 allele. CONCLUSION: Ethnic-specific R192H variation in PAX4 is associated with attention-specific cognitive impairment in Chinese with T2DM. Pending further validation studies, determining PAX4 R192H genotype may be helpful for early risk assessment of early-onset T2DM and cognitive impairment to improve diabetes care.

MODY5 Hepatocyte Nuclear Factor 1ß (HNF1ß)-Associated Nephropathy: experience from a regional monogenic diabetes referral centre in Singapore.

From our monogenic diabetes registry set-up at a secondary-care diabetes center, we identified a nontrivial subpopulation (~15%) of maturity-onset diabetes of the young (MODY) among people with young-onset diabetes. In this report, we describe the diagnostic caveats, clinical features and long-term renal-trajectory of people with HNF1B mutations (HNF1B-MODY). Between 2013 and 2020, we received 267 referrals to evaluate MODY from endocrinologists in both public and private practice. Every participant was subjected to a previously reported structured evaluation process, high-throughput nucleotide sequencing and gene-dosage analysis. Out of 40 individuals with confirmed MODY, 4 (10%) had HNF1B-MODY (harboring either a HNF1B whole-gene deletion or duplication). Postsequencing follow-up biochemical and radiological evaluations revealed the known HNF1B-MODY associated systemic-features, such as transaminitis and structural renal-lesions. These anomalies could have been missed without prior knowledge of the nucleotide-sequencing results. Interestingly, preliminary longitudinal observation (up to 15 years) suggested possibly 2 distinct patterns of renal-deterioration (albuminuric vs. nonalbuminuric chronic kidney disease). Monogenic diabetes like HNF1B-MODY may be missed among young-onset diabetes in a resource-limited routine-care clinic. Collaboration with a MODY-evaluation center may fill the care-gap. The long-term renal-trajectories of HNF1B-MODY will require further studies by dedicated registries and international consortium.

Glucokinase activating mutation causing hypoglycaemia diagnosed late in adult who fasts for Ramadhan.

SUMMARY: Activating mutation of glucokinase gene (GCK) causes resetting of insulin inhibition at a lower glucose threshold causing hyperinsulinaemic hypoglycaemia (GCK-HH). This is the first reported case who tolerated years of regular fasting during Ramadhan, presenting only with seizure and syncope now. We describe a case with GCK gene variant p.T65I diagnosed in a 51-year-old woman with hypoglycaemia unawareness even at glucose level of 1.6 mmol/L. Insulin and C-peptide levels during hypoglycaemia were suggestive of hyperinsulinism, but at a day after intravenous glucagon, hypoglycaemia occurred with low insulin and C-peptide levels, pointing against insulinoma as the underlying aetiology. Imaging studies of the pancreas and calcium arterial stimulation venous sampling were unremarkable. A review of old medical records revealed asymptomatic hypoglycaemia years ago. Genetic testing confirmed activating mutation of GCK. Hypoglycaemia was successfully controlled with a somatostatin analogue. This case highlights the importance of consideration of genetic causes of hypoglycaemia in adulthood, especially when imaging is uninformative. LEARNING POINTS: Consider genetic causes of endogenous hyperinsulinism hypoglycaemia in adulthood, especially when imaging is uninformative. Late presentation of activating mutation of GCK can occur because of hypoglycaemia unawareness. Long-acting somatostatin analogue may be useful for the treatment of activating mutation of GCK causing hypoglycaemia. Depending on the glucose level when the blood was taken, and the threshold of glucose-stimulated insulin release (GSIR), the serum insulin and C-peptide levels may be raised (hyperinsulinaemic) or low (hypoinsulinaemic) in patients with activating mutation of GCK. Glucagon may be useful to hasten the process of unmasking the low insulin level during hypoglycaemia below the GSIR level of which insulin released is suppressed.

Response to multiple glucose-lowering agents in a sib-pair with a novel HNF1α (MODY3) variant.

Maturity-onset diabetes of the young (MODY) is a genetically and clinically heterogeneous group of disorders characterised by early onset, lean, non-autoimmunity mediated, non-insulin-dependent diabetes often with autosomal-dominant inheritance and specific pharmaco-genetic response. We describe two siblings with HNF1A-MODY (MODY3) due to a novel germline variant p.(His126Asp) which segregates with diabetes in the family. However, contrary to anticipated therapeutic response, blood glucose in this sib-pair did not respond to sulphonylureas (both low and high dose), dipeptidyl peptidase-4 inhibitors (DPP-4 inhibitors), and glucagon-like peptide-1 receptor agonists (GLP-1RA), also known as incretin mimetics. The unexpected limited pharmaco-therapeutic response could potentially be unique to this specific variant and/or progressive pancreatic ß-cell failure associated with long-standing disease duration, higher BMI and glucose-toxicity. Therefore, we report a novel-variant MODY3 sib-pair with atypical pharmaco-therapeutic response i.e. resistant to multiple anti-diabetes agents namely sulphonylurea, DPP-4 inhibitors and GLP-1RA treatment.

Long-Term Observation of a Man With Severe Obesity and Undiagnosed Monogenic Diabetes Serendipitously Treated With Metabolic Surgery.

A 43-year-old man, with severe obesity (43 kg/m2) and diabetes (presumed as type 2 diabetes [T2D]), underwent vertical sleeve gastrectomy in 2009 and Roux-en-Y gastric bypass in 2013. Recently, whole exome sequencing (conducted to search for monogenic obesity) serendipitously revealed that the individual harbored a heterozygous glucokinase (GCK) variant p.(Arg422Leu) that was bioinformatically strongly predicted to be likely pathogenic. Therefore, he is likely to have concomitant maturity-onset diabetes of the young (MODY) type 2 (GCK-MODY). A retrospective evaluation of the clinical data showed that the subject was diagnosed with T2D (given his severe obesity) in 2005 and was treated with oral antidiabetic monotherapy. His hyperglycemia was mostly mild (HbA1c [hemoglobin] < 8.1%), consistent with that of MODY2, despite severe obesity. After vertical sleeve gastrectomy, complete diabetes remission (HbA1c <6.0% and fasting plasma glucose <5.6 mmol/L without use of antidiabetic medication) was achieved. The percentage of maximum body weight loss attained after surgery was 23.6%. Euglycemia was maintained during the subsequent decade, up to the last follow-up in 2019, without any sign of hypoglycemia. In conclusion, we report a decade-long clinical experience of a man with severe obesity and diabetes likely due to the coexistence of GCK-MODY and T2D, serendipitously treated with metabolic surgery. Interestingly, metabolic surgery was effective and safe for him.

Clinical experience from a regional monogenic diabetes referral centre in Singapore.

AIMS: Monogenic diabetes (also known as maturity-onset diabetes of the young or MODY) affects a subset of individuals with young-onset diabetes. We report our diagnostic work-up experience for such individuals. METHODS: Serving as a regional secondary-care diabetes centre in a multi-ethnic population, we receive referrals to evaluate MODY from endocrinologists in both public and private practice. Key criteria for consideration of genetic-testing are onset age ≤ 35, negative GAD antibody, no history of diabetic ketoacidosis, strong family history of diabetes and BMI < 32.5 kg/m2. A monogenic diabetes registry was set up since 2017 to study their disease trajectories. RESULTS: We identified 30 out of 175 (17.1%) individuals with likely pathogenic/pathogenic variants. Importantly, 29 out of 30 (96.7%) occurred in clinically actionable genes. A continuous scale combining BMI, hs-CRP and HDL provided 80% (P < 0.001) diagnostic accuracy for MODY in our cohort, achieving a negative predictive value of 0.93 and sensitivity at 0.76. Subtyping MODY prior to genetic testing (if desired) will require specialist domain knowledge and additional biomarkers due to its genetic heterogeneity. CONCLUSIONS: Through systematic and structured evaluation, the prevalence of MODY is non-trivial (17.1%) in a referral centre. Diagnostic algorithm combining clinical criteria and readily available biomarkers can support clinical decision for MODY genetic testing.

Association of traditional and novel measures of central obesity with cognitive performance in older multi-ethnic Asians with type 2 diabetes.

Literature evaluating the relationship between central obesity and cognitive deficits in type 2 diabetes (T2DM) remains scarce. This cross-sectional analysis explored the association of novel and traditional central obesity measures with cognitive performance in older (aged ≥60 years) non-demented multi-ethnic Asians with T2DM, including a stratified analysis by body mass index (BMI). Cognitive function was assessed using the Repeatable Battery for the Assessment of Neuropsychological Status. Central obesity measures including visceral fat area (VFA), waist circumference, waist:hip ratio, waist:height ratio, abdominal volume index, body roundness index and conicity index were measured and/or computed. In our cohort (N = 677; mean age = 67 ± 5 years, 51.7% men), VFA emerged as an associate of overall cognitive performance after covariate adjustment and Bonferroni correction (ß = -.10, 95% CI = -0.18, -0.03), outperforming the other adiposity indices. Specifically, VFA was inversely associated with delayed memory and language scores. Additionally, compared with normal-weight individuals, excess visceral obesity (VFA ≥100 cm2 ) was independently associated with lower cognitive scores to a greater extent in normal BMI (<23 kg/m2 ) adults than in those with high BMI (≥23 kg/m2 ). Assessment and management of visceral adiposity may help to prevent cognitive decline in older people with T2DM, and reduce the global burden of dementia in ageing populations.

The morphogenic function of E-cadherin-mediated adherens junctions in epithelial ovarian carcinoma formation and progression.

E-cadherin expression is unusually regulated in epithelial ovarian carcinoma. It is not expressed in poorly cohesive ovarian surface epithelial (OSE) target cells, but is expressed in cohesive pre-malignant lesions and in highly cohesive, well-differentiated tumors where it is membrane associated, presumably in adherens junctions. E-cadherin expression is subsequently suppressed, or its function is disrupted, in late-stage invasive tumors. Here, we observed that increased E-cadherin expression in ovarian carcinoma cells was associated with increased E-cadherin promoter activity, increased adherens junction formation, decreased beta-catenin signaling-dependent LEF-1 activity, and the generation of cohesive spheroids in basement membrane gel culture. Forced expression of wild-type E-cadherin in immortalized OSE cells initiated adherens junction formation, decreased LEF-1 activity, decreased the mesenchymal migration that is a characteristic of OSE cells that have been maintained in monolayer culture, and induced the formation of cohesive spheroids in basement membrane gels. Conversely, forced expression of a dominant-negative E-cadherin mutant in ovarian carcinoma cells disrupted adherens junctions, increased mesenchymal cell migration, and prevented spheroidal morphogenesis without altering LEF-1 signaling. Therefore, in addition to suppressing late-stage tumor progression, E-cadherin-mediated adherens junctions may also contribute to the initial emergence of a cohesive morphogenic phenotype that is a hallmark of differentiated epithelial ovarian carcinoma.

Educational pamphlets for improving uptake of cancer screening: a systematic review.

INTRODUCTION The effectiveness of cancer screening programmes is highly dependent on screening uptake. Many interventions have been tested to increase screening uptake. AIM The goal of this study was to evaluate the effectiveness of cancer screening pamphlets as a standalone intervention. The outcome of interest was uptake of cancer screening tests. METHODS A systematic review was performed on the effectiveness of pamphlets compared to usual care without pamphlets. We searched five databases for research papers in English from 2000 up to May 2019. Randomised controlled trials were included. This research group independently selected studies, extracted data, assessed risk of bias and then compared the information as a group. RESULTS A total of nine trials involving 4912 participants met our inclusion criteria, of which five were about colorectal cancer screening, three were about prostate cancer screening and one was about lung cancer screening. Five of the nine trials showed that pamphlets alone increased uptake significantly, while the remaining four trials did not show significant effects. DISCUSSION There is some evidence that pamphlets increase uptake for cancer screenings, especially for colorectal cancer. Due to the small number of studies in this area, generalisability could be limited.

Precision medicine for a man presented with diabetes at 2-month old.

A 22-year-old man was referred for continuation of diabetes mellitus treatment. He was first diagnosed with diabetes mellitus 2 months after birth, when he failed to thrive and showed symptoms of diabetic ketoacidosis. There was no family history of diabetes mellitus. The patient did not exhibit the full set of features to be qualified for any developmental delay, epilepsy and neonatal diabetes mellitus (DEND) syndrome. Insulin replacement therapy was initiated; however, management was challenged by wide glycemic excursion, hypoglycemic unawareness and insulin-associated cutaneous lipo-hypertrophy. Re-evaluation, including genetic testing, revealed a heterozygous missense p.Arg201Cys variation in the KCNJ11 gene encoding the potassium channel subunit Kir6.2. Successful treatment conversion from insulin to glibenclamide was achieved over an extended period of 2 months (up-titrating to a dose of 1.0 mg/kg) in this patient despite his long diabetes duration of 27 years with elimination of hypoglycemia unawareness and achievement of excellent glycemic control sustained over more than 5 years. This case highlights the importance of after having secured a firm genetic diagnosis, to undertake conversion to sulphonylurea with careful dose titration and perseverance over months. Confirmation of variants with functional implications by genetic testing in patients suspected of neonatal diabetes is important for accurate molecular diagnosis and precision-treatment strategy with optimal outcome.