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The biology of breast cancer response to neoadjuvant therapy is underrepresented in the literature and provides a window-of-opportunity to explore the genomic and microenvironment modulation of tumours exposed to therapy. Here, we characterised the mutational, gene expression, pathway enrichment and tumour-infiltrating lymphocytes (TILs) dynamics across different timepoints of 35 HER2-negative primary breast cancer patients receiving neoadjuvant eribulin therapy (SOLTI-1007 NEOERIBULIN-NCT01669252). Whole-exome data (N = 88 samples) generated mutational profiles and candidate neoantigens and were analysed along with RNA-Nanostring 545-gene expression (N = 96 samples) and stromal TILs (N = 105 samples). Tumour mutation burden varied across patients at baseline but not across the sampling timepoints for each patient. Mutational signatures were not always conserved across tumours. There was a trend towards higher odds of response and less hazard to relapse when the percentage of subclonal mutations was low, suggesting that more homogenous tumours might have better responses to neoadjuvant therapy. Few driver mutations (5.1%) generated putative neoantigens. Mutation and neoantigen load were positively correlated (R2 = 0.94, p = R2 = 0.16, p = 0.02). An enrichment in pathways linked to immune infiltration and reduced programmed cell death expression were seen after 12 weeks of eribulin in good responders. VEGF was downregulated over time in the good responder group and FABP5, an inductor of epithelial mesenchymal transition (EMT), was upregulated in cases that recurred (p

Background The COVID-19 pandemic has seen major shifts in the delivery of health care across the world, including adoption of telemedicine. We present a survey of patient experience with telemedicine for the treatment of breast cancer. Methods A questionnaire designed to assess patient satisfaction with telemedicine was distributed to all patients who underwent surgery at the Providence Breast Centre (PBC) for breast cancer or benign/high-risk lesions with surgery follow-up dates between October 13 and December 31, 2020. Surveys were conducted via phone or at in-person follow-ups. Results A total of 123 of 172 (72%) eligible patients completed the survey; 85% of these patients enjoyed their telemedicine consultation, 93% found there was enough time for dialogue, 66% would choose to have a telemedicine consultation again, 79% would recommend telemedicine at PBC to a friend or family member, and 92% found Zoom© easy to use. When asked whether they prefer a telemedicine initial consultation over an in-person, 28% of patients agreed. When patients are analyzed according to their home address, those more than 10-km away from PBC prefer telemedicine over in-person appointments (37%) more often than those who live less than 10-km away (23%) (p = 0.045). Conclusions Patients report a high level of satisfaction with telemedicine. It may be worthwhile to continue telemedicine beyond the pandemic era, due to its convenience, efficiency, and low-cost while keeping patients, physicians, and office staff safe. It also may be more useful in large geographic areas, such as British Columbia to increase access to care.

Dilated cardiomyopathy (DCM) is one of the most common cardiac phenotypes caused by mutations of lamin A/C (LMNA) gene in humans. In our study, a cohort of 57 patients who underwent heart transplant for dilated cardiomyopathy was screened for variants in LMNA. We identified a synonymous variant c.936G>A in the last nucleotide of exon 5 of LMNA in a DCM family. Clinically, the LMNA variant carriers presented with severe familial DCM, conduction disease, and high creatine-kinase level. The LMNA c.936G>A variant is novel and has not been reported in current genetic variant databases. Sanger sequencing results showed the presence of LMNA c.936G>A variant in the genomic DNA but not in the cDNA derived from one family member's heart tissue. Real-time quantitative polymerase chain reaction showed significantly lower LMNA mRNA levels in the patient's heart compared to the controls, suggesting that the c.936G>A LMNA variant resulted in reduced mRNA and possibly lower protein expression of LMNA. These findings expand the understanding on the association between synonymous variant of LMNA and the molecular pathogenesis in DCM patients.

Background Ultimate Frisbee is a non-contact, self-refereed team sport that is rapidly gaining popularity in Hong Kong. As it is a physically demanding competition, it can result in substantial injury risk. However, the injury epidemiology data in Hong Kong remains lacking. The aim of this study is to identify and analyse the injury prevalence and risk factors for Ultimate Frisbee players in Hong Kong. Methods Online self-reported surveys were collected from participants through the Hong Kong Flying Disc Federation for the 2019 season. Data was collected on injury type, location, nature, severity and onset. Injury incidence rates (IRs) were calculated as injuries per 1000 h of athlete-exposures (AEs). Incidence rate ratios were determined to compare IRs with 95% confidence intervals, which were used to calculate differences. In addition, analysis on IR will be made on comparing between training and tournament. Results Response rate of 75.6% was achieved, of which 59 entries were included for analysis. We observed 54 injuries over 9412 AEs for a total IR of 5.74 per 1000 h of AEs. The injury prevalence is 62.7%, with both men and women having similar incidence (IRR = 1.161, 95% CI = 0.63, 2.14, p = 0.63). The most common injuries were in the lower limb (61.1%). Cutting was the most frequent injury mechanism (23.7%). The risk of injury during training is 3 times less compared to during tournament (IRR = 0.03, 95% CI = 0.18, 0.60, p Conclusion Our preliminary findings provide evidence that majority of Ultimate injuries in Hong Kong players involved the lower extremity with injuries occurring more in tournaments than training. This study is an important first step to provide the groundwork for tailoring prevention strategies to minimize injuries in Ultimate Frisbee.

BACKGROUND: Driving is a complex task requiring multiple cognitive domains and the musculoskeletal system. Cognitive dysfunction is associated with driving impairment. Dialysis patients are known to have a high prevalence of cognitive impairment and other comorbidities, and may be at risk of driving impairment. No Australian guidelines address driving safety in dialysis patients. AIMS: To estimate the proportion of dialysis patients who were driving and those at risk of driving impairment, and to investigate the agreement between objective and subjective markers of risk. METHODS: This single-centre study involved dialysis patients voluntarily completing two questionnaires relating to risk of driving impairment; the first questionnaire focussed on objective markers, and the second questionnaire focussed on subjective markers. Risk of driving impairment was established using pre-determined criteria, and the agreement between objective and subjective markers was estimated using Cohen kappa. RESULTS: A total of 44.8% (99/221) of patients participated; 76.8% (76/99) of participants were driving, and 76.3% (58/76) of drivers were at risk of driving impairment. Factors associated with at-risk driving included post dialysis dizziness, leg weakness or numbness, falling asleep while driving and hypoglycaemia. Sixteen patients reported collisions since commencing dialysis. The questionnaires displayed slight agreement (Cohen kappa = 0.20) between objective and subjective markers. CONCLUSIONS: Dialysis patients are at risk of driving impairment based on self-reported questionnaire responses. Discrepancies between patients' perceptions and objective markers were apparent. Further research into appropriate risk assessments, as well as development of guidelines to aid in determining driving safety in dialysis patients, is needed.

Chemotherapy can induce toxicity in the central and peripheral nervous systems and result in chronic adverse reactions that impede continuous treatment and reduce patient quality of life. There is a current lack of research to predict, identify, and offset drug-induced neurotoxicity. Rapid and accurate assessment of potential neuropathy is crucial for cost-effective diagnosis and treatment. Here we report dynamic near-infrared upconversion imaging that allows intraneuronal transport to be traced in real time with millisecond resolution, but without photobleaching or blinking. Drug-induced neurotoxicity can be screened prior to phenotyping, on the basis of subtle abnormalities of kinetic characteristics in intraneuronal transport. Moreover, we demonstrate that combining the upconverting nanoplatform with machine learning offers a powerful tool for mapping chemotherapy-induced peripheral neuropathy and assessing drug-induced neurotoxicity.

Anti-Wolbachia therapy has been identified as a viable treatment for combating filarial diseases. Phenotypic screening revealed a series of pyrazolopyrimidine hits with potent anti-Wolbachia activity. This paper focuses on the exploration of the SAR for this chemotype, with improvement of metabolic stability and solubility profiles using medicinal chemistry approaches. Organic synthesis has enabled functionalization of the pyrazolopyrimidine core at multiple positions, generating a library of compounds of which many analogues possess nanomolar activity against Wolbachia in vitro with improved DMPK parameters. A lead compound, 15f, was selected for in vivo pharmacokinetics (PK) profiling in mice. The combination of potent anti-Wolbachia activity in two in vitro assessments plus the exceptional oral PK profiles in mice puts this lead compound in a strong position for in vivo proof-of-concept pharmacodynamics studies and demonstrates the strong potential for further optimization and development of this series for treatment of filariasis in the future.

Human respiratory syncytial virus (RSV) is one of the major causes of childhood acute lower respiratory tract infection worldwide. Autophagy is an intracellular pathway involved in nutrient recycling. Recently, autophagy has been reported to play a role in regulating host cytokine response to several viruses, including vesicular stomatitis virus and human immunodeficiency virus. Previous in vivo studies using mouse model has shown that inhibition of autophagy reduces RSV-induced cytokine production. However, the role of autophagy in modulating RSV-induced cytokine response in human cells has not been reported. We investigated the role of autophagy in regulating the production of the cytokines C-X-C motif ligand 8 (CXCL8) and C-C motif ligand 5 (CCL5), in RSV-infected human bronchial epithelium BEAS-2B cells. Fluorescent microscopic analysis showed that RSV infection induced autophagosome formation in BEAS-2B cells. This autophagy inducing ability of RSV was further confirmed by flow cytometry. The effects of pharmacological inhibition of autophagy by SAR405 or chloroquine on cell death and cytokine release were quantified using lactate dehydrogenase assay and enzyme-linked immunosorbent assay (ELISA), respectively. We found that SAR405 or chloroquine did not cause cell death. Importantly, ELISA analysis showed that pharmacological inhibition of autophagy by SAR405 or chloroquine did not affect the productions of both CXCL5 and CXCL8. In contrast to the previous studies using mouse model, our data suggest that pharmacological inhibition of autophagy may not be a suitable strategy in controlling RSV-induced airway inflammation.

Novel biomarkers for HCC surveillance in cirrhotic patients are urgently needed. Exosomes and their lipid content in particular represent potentially valuable noninvasive diagnostic biomarkers. We isolated exosomes from plasma of 72 cirrhotic patients, including 31 with HCC. Exosomes and unfractionated plasma were processed for untargeted lipidomics using ultra–high-resolution mass spectrometry. A total of 2,864 lipid species, belonging to 52 classes, were identified. Both exosome fractionation and HCC diagnosis had significant impact on the lipid profiles. Ten lipid classes were enriched in HCC exosomes compared with non-HCC exosomes. Dilysocardiolipins were detected in 35% of the HCC exosomes but in none of the non-HCC exosomes (P < 0.001). Cardiolipins and sphingosines had the highest differential effects (fold change of 133.08, q = 0.001 and 38.57, q < 0.001, respectively). In logistic regression analysis, high abundances of exosomal sphingosines, dilysocardiolipins, lysophosphatidylserines, and (O-acyl)-1-hydroxy fatty acids were strongly associated with HCC [OR (95% confidence interval (CI)), 271.1 (14.0–5,251.9), P < 0.001; 46.5 (2.3–939.9), P = 0.012; 14.9 (4.3–51.2), P < 0.001; 10.3 (3.2–33.1), P < 0.001]. Four lipid classes were depleted in HCC exosomes compared with non-HCC exosomes. In logistic regression analysis, lack of detection of sulfatides and acylGlcSitosterol esters was strongly associated with HCC [OR (95% CI): 215.5 (11.5–4,035.9), P < 0.001; 26.7 (1.4–528.4), P = 0.031]. These HCC-associated changes in lipid composition of exosomes reflected alterations in glycerophospholipid metabolism, retrograde endocannabinoid signaling, and ferroptosis. In conclusion, this study identified candidate biomarkers for early detection of HCC as well as altered pathways in exosomes that may contribute to tumor development and progression. Prevention Relevance: This study identifies lipids in circulating exosomes, that could serve as biomarkers for the early detection of hepatocellular carcinoma as well as altered pathways in exosomes that may contribute to tumor development and progression.

Contains fulltext : 237483.pdf (Publisher’s version ) (Open Access) BACKGROUND: d-lactate, one of the isomers of lactate, exists in a low concentration in healthy individuals and it can be oxidized to pyruvate catalyzed by d-lactate dehydrogenase. Excessive amount of d-lactate causes d-lactate acidosis associated with neurological manifestations. METHODS AND RESULTS: We report here a patient with developmental delay, cerebellar ataxia, and transient hepatomegaly. Enzyme analysis in the patient's skin fibroblast showed decreased mitochondrial complex IV activity. Using whole exome sequencing, we identified compound heterozygous variants in the LDHD gene, which encodes the d-lactate dehydrogenase, consisting of a splice site variant c.469+1dupG and a missense variant c.752C>T, p.(Thr251Met) which are pathogenic and likely pathogenic respectively according to the American College of Medical Genetics and Genomics (ACMG) classification. The serum d-lactate level was subsequently detected to be elevated (0.61 mmol/L, reference value: 0-0.25 mmol/L). CONCLUSION: This is the third report on LDHD mutations associated with d-lactate elevation and was first reported to have decreased mitochondrial complex IV activity. The study provides more information on this rare metabolic condition but the association of LDHD deficiency with the clinical presentations requires further investigations.

[Image: see text] Synthetic endoperoxide antimalarials, such as 1,2,4-trioxolanes and 1,2,4,5-tetraoxanes, are promising successors for current front-line antimalarials, semisynthetic artemisinin derivatives. However, limited solubility of second-generation analogues in biological-relevant media represents a barrier in clinical development. We present methodology for the synthesis of nonlinear analogues of second-generation tetraoxane antimalarials E209 and N205 to investigate reduced molecular symmetry on in vitro antimalarial activity and physicochemical properties. While maintaining good antimalarial activity and metabolic stability, head-to-head comparison of linear and nonlinear counterparts showed up to 10-fold improvement in FaSSIF solubility for three of the four analogues studied. Pharmacokinetic studies in rats comparing a selected nonlinear analogue 14a and its parent N205 showed improvement on oral absorption and exposure in vivo with more than double the AUC and a significant increase in oral bioavailability (76% versus 41%). These findings provide support for further in vivo efficacy studies in preclinical animal species.

AIMS To determine the prevalence and predictors of medication non-adherence among older community-dwelling people with at least one chronic disease in Singapore. DESIGN A single-centre cross-sectional study. METHODS The study was conducted in the largest tertiary public hospital in Singapore between May 2019 and December 2019. The community nurses of the hospital recruited a total of 400 community-dwelling older people aged ≥60 years old, who were diagnosed with at least one chronic disease and prescribed with at least one long-term medication. Medication non-adherence was assessed using the self-report 5-item Medication Adherence Report Scale, operationalized as a score of

BACKGROUND Our health care is facing with the challenges of bed crunch and increasing number of patients with prolonged hospital stay. AIMS This study aimed to determine factors contributing to the prolonged hospital stay in a tertiary hospital in Singapore. METHODS A random sample of 600 medical records of patients' staying in hospital for more than 21 days was retrieved. The reasons for their prolonged hospital stay were categorized into 'medically unfit' and 'medically fit'. RESULTS The top three reasons for prolonged hospital stay among the 'medically unfit' group were ongoing medical treatment, surgical interventions and receiving intravenous chemotherapy/radiotherapy. The top three reasons for the 'medically fit' group were waiting for community hospital bed, waiting for a new caregiver and undecided on discharge disposition. CONCLUSION The results inform health care stakeholders in planning measures to minimize the incidence of unnecessary prolonged hospitalization for optimal health care resource utilization. IMPLICATIONS OF NURSING MANAGEMENT Ineffective discharge planning can lead to serious adverse outcomes such as hospital readmission and prolonged hospital stay. Patient navigators have a crucial role in facilitating safe, smooth and timely discharge of patients from acute care hospital to community. Understanding the reasons behind extended hospitalization is essential in order to better provide support.

Heterozygous HNF1A gene mutations can cause maturity onset diabetes of the young 3 (MODY3), characterized by insulin secretion defects. However, specific mechanisms of MODY3 in humans remain unclear due to lack of access to diseased human pancreatic cells. Here, we utilize MODY3 patient-derived human induced pluripotent stem cells (hiPSCs) to study the effect(s) of a causal HNF1A+/H126D mutation on pancreatic function. Molecular dynamics simulations predict that the H126D mutation could compromise DNA binding and gene target transcription. Genome-wide RNA-Seq and ChIP-Seq analyses on MODY3 hiPSC-derived endocrine progenitors reveal numerous HNF1A gene targets affected by the mutation. We find decreased glucose transporter GLUT2 expression, which is associated with reduced glucose uptake and ATP production in the MODY3 hiPSC-derived β-like cells. Overall, our findings reveal the importance of HNF1A in regulating GLUT2 and several genes involved in insulin secretion that can account for the insulin secretory defect clinically observed in MODY3 patients., Heterozygous HNF1A mutations can give rise to maturity onset diabetes of the young 3 (MODY3), characterized by insulin secretion defects. Here the authors show that MODY3-related HNF1A mutation in patient hiPSCderived pancreatic cells decreases glucose transporter GLUT2 expression due to compromised DNA binding.

Background To establish a set of consensus statements for the management of metastatic renal cell carcinoma, a total of 12 urologists and clinical oncologists from two professional associations in Hong Kong formed an expert consensus panel. Methods Through a series of meetings and using the modified Delphi method, the panelists presented recent evidence, discussed clinical experiences, and drafted consensus statements on several areas of focus regarding the management of metastatic renal cell carcinoma. Each statement was eventually voted upon by every panelist based on the practicability of recommendation. Results A total of 46 consensus statements were ultimately accepted and established by panel voting. Conclusions Derived from recent evidence and expert insights, these consensus statements were aimed at providing practical guidance to optimize metastatic renal cell carcinoma management and promote a higher standard of clinical care.

This case demonstrates the challenges encountered in a case of Neuroleptic Malignant Syndrome in a young woman with moderate Intellectual Disability.

Background Cancer can cause undesired side effects that can significantly alter patients' perceived stress and mindfulness. The integration of nonpharmacologic, complementary health interventions, such as mindful breathing, is potentially useful in reducing stress and promoting the well-being of patients during treatment. Objectives This study examined the effects of a five-minute mindful breathing practice performed three times per day for three months on perceived stress and mindfulness among patients with cancer. Methods This longitudinal, randomized controlled study used a two-group, pre-/post-study design. Patients with distress scores of 4 or higher were randomized into two study arms. Participants in the intervention group were educated on mindfulness and guided on how to perform a five-minute mindful breathing practice. Perceived stress and mindfulness were assessed at baseline, one month postintervention, and three months postintervention. Findings Both groups had no significant difference in perceived stress and mindfulness scores at baseline. At three months, the intervention group reported a significant reduction in stress and an increase in mindfulness.

Extensive studies have shown that cancer cells have specific nutrient auxotrophy and thus have much a higher demand for certain nutrients than normal cells. Amino acid deprivation has attracted much attention in cancer therapy with positive outcomes from clinical trials. Arginine, as one of the conditionally essential amino acids, plays a pivotal role in cellular division and metabolism. Since many types of cancer cells exhibit decreased expression of argininosuccinate synthetase and/or ornithine transcarbamylase, they are auxotrophic for arginine, which makes arginine deprivation an accessible choice for cancer treatment. Arginine deiminase (ADI) and human arginase (hArg) are the two major protein drugs used for arginine deprivation and are undergoing many clinical trials. However, the clinical application of ADI and hArg is facing some common problems, including their short half-lives, immunogenicity and inconsistent production, which underlines the importance of improving these drugs using protein engineering techniques. Thus, we systematically review the latest studies of protein engineering and anti-cancer studies based on in vitro, in vivo and clinical models of ADI and hArg, and we include the latest studies on drug combinations consisting of ADI/hArg with chemotherapeutic drugs.

Purpose of review Dilated cardiomyopathy (DCM), which include genetic and nongenetic forms, is the most common form of cardiomyopathy. DCM is characterized by left ventricular or biventricular dilation with impaired contraction. In the United States, DCM is a burden to healthcare that accounts for approximately 10,000 deaths and 46,000 hospitalizations annually. In this review, we will focus on the genetic forms of DCM and on recent advances in the understanding of cytoskeletal, sarcomeric, desmosomal, nuclear membrane, and RNA binding genes that contribute to the complexity and genetic heterogeneity of DCM. Recent findings Although mutations in TTN remain the most common identifiable cause of genetic DCM, there is a growing appreciation for arrhythmogenic-prone DCM due to mutations in LMNA, desmosomal genes, and the recently described FLNC gene encoding the structural filamin C protein. Mutations in RBM20 highlight the relevance of RNA splicing regulation in the pathogenesis of DCM. Although expanded genetic testing has improved access to genetic diagnostic studies for many patients, the molecular mechanisms in the pathogenesis of the disease remained largely unknown. Summary : The identification of the molecular causes and subsequent insight into the molecular mechanisms of DCM is expanding our understanding of DCM pathogenesis and highlights the complexity of DCM and the need to develop multifaceted strategies to treat the various causes of DCM.

Objectives: A wealth of literature has established risk factors for social isolation among older people; however, much of this research has focused on community-dwelling populations. Relatively little is known about how risk of social isolation is experienced among those living in long-term care (LTC) homes. We conducted a scoping review to identify possible risk factors for social isolation among older adults living in LTC homes. Methods: A systematic search of five online databases retrieved 1535 unique articles. Eight studies met the inclusion criteria. Results: Thematic analyses revealed that possible risk factors exist at three levels: individual (e.g., communication barriers), systems (e.g., location of LTC facility), and structural factors (e.g., discrimination). Discussion: Our review identified several risk factors for social isolation that have been previously documented in literature, in addition to several risks that may be unique to those living in LTC homes. Results highlight several scholarly and practical implications.

Funder: Cancer Research UK, Funder: Wellcome Trust, DNA methylation is aberrant in cancer, but the dynamics, regulatory role and clinical implications of such epigenetic changes are still poorly understood. Here, reduced representation bisulfite sequencing (RRBS) profiles of 1538 breast tumors and 244 normal breast tissues from the METABRIC cohort are reported, facilitating detailed analysis of DNA methylation within a rich context of genomic, transcriptional, and clinical data. Tumor methylation from immune and stromal signatures are deconvoluted leading to the discovery of a tumor replication-linked clock with genome-wide methylation loss in non-CpG island sites. Unexpectedly, methylation in most tumor CpG islands follows two replication-independent processes of gain (MG) or loss (ML) that we term epigenomic instability. Epigenomic instability is correlated with tumor grade and stage, TP53 mutations and poorer prognosis. After controlling for these global trans-acting trends, as well as for X-linked dosage compensation effects, cis-specific methylation and expression correlations are uncovered at hundreds of promoters and over a thousand distal elements. Some of these targeted known tumor suppressors and oncogenes. In conclusion, this study demonstrates that global epigenetic instability can erode cancer methylomes and expose them to localized methylation aberrations in-cis resulting in transcriptional changes seen in tumors.

Aim Sex differences are well documented in schizophrenia, but have been much less studied in at-risk mental state (ARMS) for psychosis. We aimed to examine sex differences in symptomatology, cognition, social and role functioning in individuals with ARMS, with specific focus on clarifying relationships between sex, negative symptoms and functioning. Methods One hundred and seventy-seven Chinese participants aged 15-40 years with ARMS were recruited from a specialized early intervention service in Hong Kong. ARMS status was verified by Comprehensive Assessment of At-Risk Mental State. Assessments encompassing symptom profiles, a brief battery of cognitive tests and social and role functioning were conducted. Brief Negative Symptom Scale was adapted to measure negative symptoms at the level of five core domains. Results Males with ARMS exhibited significantly poorer social functioning and more severe asociality of negative symptoms than female counterparts. Mediation analysis revealed that sex difference in social functioning became statistically insignificant when asocality was included in the model, indicating that asociality mediated the relationship between sex and social functioning. No sex differences were observed in other core domains of negative symptoms, other symptom dimensions, cognitive measures and role functioning. Conclusions This study suggests that sex differences in ARMS may be less pronounced that those observed in established psychotic disorders. Our findings of differential pattern of asociality between sexes and its mediating role on sex difference in social functioning underscore the importance in investigating negative symptoms at a separable domain-level. Further research is required to identify sex-specific predictors of longitudinal outcomes in at-risk populations.

This short article presents the plight of grassroots under the Covid-19 pandemic, which has been in the third wave from mid-July 2020. Like in many other places, the outbreak has caused economic downturn, and intensified stress about health and rising unemployment. The disadvantaged groups are suffering the most, which shows the problem of social inequality in the community. The roles of community social work in Hong Kong are highlighted to show how social workers can contribute to crisis management and empowerment of the deprived.

Purpose: Endocrine resistance remains a major clinical challenge in estrogen receptor (ER)–positive breast cancer. Despite the encouraging results from clinical trials for the drugs targeting known survival signaling, relapse is still inevitable. There is an unmet need to discover new drug targets in the unknown escape pathways. Here, we report Nemo-like kinase (NLK) as a new actionable kinase target that endows previously uncharacterized survival signaling in endocrine-resistant breast cancer. Experimental Design: The effects of NLK inhibition on the viability of endocrine-resistant breast cancer cell lines were examined by MTS assay. The effect of VX-702 on NLK activity was verified by kinase assay. The modulation of ER and its coactivator, SRC-3, by NLK was examined by immunoprecipitation, kinase assay, luciferase assay, and RNA sequencing. The therapeutic effects of VX-702 and everolimus were tested on cell line- and patient-derived xenograft (PDX) tumor models. Results: NLK overexpression endows reduced endocrine responsiveness and is associated with worse outcome of patients treated with tamoxifen. Mechanistically, NLK may function, at least in part, via enhancing the phosphorylation of ERα and its key coactivator, SRC-3, to modulate ERα transcriptional activity. Through interrogation of a kinase profiling database, we uncovered and verified a highly selective dual p38/NLK inhibitor, VX-702. Coadministration of VX-702 with the mTOR inhibitor, everolimus, demonstrated a significant therapeutic effect in cell line-derived xenograft and PDX tumor models of acquired or de novo endocrine resistance. Conclusions: Together, this study reveals the potential of therapeutic modulation of NLK for the management of the endocrine-resistant breast cancers with active NLK signaling.

Purpose: Luminal B breast tumors are more aggressive estrogen receptor–positive (ER+) breast cancers characterized by aggressive clinical behavior and a high risk of metastatic dissemination. The underlying pathologic molecular events remain poorly understood with a paucity of actionable genetic drivers, which hinders the development of new treatment strategies. Experimental Design: We performed large-scale RNA sequencing analysis to identify chimerical transcripts preferentially expressed in luminal B breast cancer. The lead candidate was validated by reverse transcription PCR in breast cancer tissues. The effects of inducible ectopic expression or genetic silencing were assessed by phenotypic assays such as MTS, transwell, and transendothelial migration assays, and by clonogenic assays to assess MEK inhibitor sensitivity. Subcellular fractionation, Western blots, and immunoprecipitation were performed to characterize the protein products and elucidate the engaged mechanisms. Results: Here we report a novel tumor-specific chimeric transcript RAD51AP1-DYRK4 preferentially expressed in luminal B tumors. Analysis of 200 ER+ breast tumors detected RAD51AP1-DYRK4 overexpression in 19 tumors (9.5%), which is markedly enriched in the luminal B tumors (17.5%). Ectopic expression of RAD51AP1-DYRK4, but not wild-type RAD51AP1, leads to marked activation of MEK/ERK signaling, and endows increased cell motility and transendothelial migration. More importantly, RAD51AP1-DYRK4 appears to endow increased sensitivity to the MEK inhibitor trametinib through attenuating compensatory activation of HER2/PI3K/AKT under MEK inhibition. Conclusions: This discovery sheds light on a new area of molecular pathobiology of luminal B tumors and implies potential new therapeutic opportunities for more aggressive breast tumors overexpressing this fusion.

A 30-kb deletion that eliminates the coding region of APOBEC3B (A3B) is >5 times more common in women of Asian compared to European descent. This polymorphism creates a chimera with the APOBEC3A (A3A) coding region and A3B 3'UTR, and is associated with an increased risk for breast cancer in Asian women. Here, we explored the relationship between the A3B deletion polymorphism with tumour characteristics in Asian women. Using whole exome and whole transcriptome sequencing data of 527 breast tumours, we report that germline A3B deletion polymorphism leads to expression of the A3A-B hybrid isoform and increased APOBEC-associated somatic hypermutation. Hypermutated tumours, regardless of A3B germline status, were associated with the Her2 molecular subtype and PIK3CA mutations. Compared to non-hypermutated tumours, hypermutated tumours also had higher neoantigen burden, tumour heterogeneity and immune activation. Taken together, our results suggest that the germline A3B deletion polymorphism, via the A3A-B hybrid isoform, contributes to APOBEC-mutagenesis in a significant proportion of Asian breast cancers. In addition, APOBEC somatic hypermutation, regardless of A3B background, may be an important clinical biomarker for Asian breast cancers. This article is protected by copyright. All rights reserved.

Contains fulltext : 241407.pdf (Publisher’s version ) (Open Access) OBJECTIVE: Dravet syndrome (DS) is a severe and intractable form of epilepsy with prolonged seizures which may evolve to other seizure types and associated with mild-to-severe intellectual disabilities. Fibroblast growth factor 21 (FGF-21) is a stress hormone mediating metabolic and oxidative stress and circulating level of FGF-21 had been shown to increase in some patients with impairment of oxidative phosphorylation in muscles. In DS, FGF-21 is of interest for further study as mitochondrial oxidative stress was identified previously in patients. METHODS: Plasma FGF-21 levels were compared between 22 DS patients and 22 normal controls, and their clinical characteristics of DS patients at the time of plasma sampling were studied retrospectively. Besides, the relationships of FGF-21 level with intellectual development, seizure frequency, valproate treatment, and types of SCN1A mutations were analyzed. Logarithmic transformation of FGF-21 levels was performed before comparison and statistical analysis. RESULTS: Mean of log(10) FGF-21 level was significantly higher in DS patients when comparing with normal controls (P = .0042). Mean of log(10) FGF-21 level was significantly higher in DS patients with normal-to-mild ID versus mild-to-severe ID (P = .0193) and with valproate treatment versus without valproate treatment (P = .015). No significant difference was shown in FGF-21 level in DS patients with missense versus truncating SCN1A variants, and no correlation could be demonstrated between seizure frequency and FGF-21 level. SIGNIFICANCE: Significantly higher level of plasma FGF-21 was identified in DS patients. The high FGF-21 levels were shown to be associated with developmental outcome and valproate treatment. These results support further investigation on the relationship of FGF-21 with the clinical outcomes of DS and other related mechanism which is important for possible therapeutic development for this epileptic encephalopathy.

Background With school closures and social isolation imposed by the COVID-19 pandemic, both children and parents in Hong Kong have been forced to stay at home for extended periods of time Besides the disease itself growing globally, this pandemic has inflicted many other healthcare problems This study aims to look at the impact of COVID-19 pandemic on paediatric surgical accidents Methods A retrospective review of all patients under 18?years of age admitted to a tertiary paediatric surgical unit with accidents was done between January to May 2020 (COVID-19 social isolation period) Comparison was made with cases between January to May 2018 and 2019 Inclusion diagnosis include foreign body ingestion(FBI), scald injury, animal bite, and fall Demographic data including age and gender, details of injury and treatment, and length of hospitalization were recorded Statistical analysis was performed by Fisher Exact test and statistical significance was defined as P?≤?0 05 Results A total of 35 patients were admitted during the period 1-5/2020 compared to 28 patients in 1-5/2019 and 16 patients in 1-5/2018 Median age at presentation is 3?years Diagnosis include FBI, animal bite, scald injury and fall Thirteen required surgical intervention including OGD (20%), wound debridement (13%), wound suturing (67%) Mean length of hospital stay was 2 89?days The proportion of domestic accidents in 2020 increased compared with the same period in 2018 and 2019 (P-values = 0 0001, 0 0259) Non-food foreign body ingestions at home during COVID19 increased significantly (P-values = 0 0018, 0 0223) Surgical intervention required for domestic accidents in 2020 also increased (P-values = 0 1223, 0 107) Conclusion The social isolation imposed by the COVID-19 pandemic has caused an increase in paediatric domestic accidents requiring admission to our surgical ward Governments and healthcare authorities should proactively implement appropriate intervention programs and better plan resources to prevent these domestic accidents during lockdown

KCNQ2 mutations encompass a wide range of phenotypes, ranging from benign familial neonatal seizure to a clinical spectrum of early-onset epileptic encephalopathy that occurs in the early neonatal period. We report an infant with KCNQ2 encephalopathy presenting as neonatal seizure, initially controlled by two anticonvulsants. Electroencephalogram (EEG) showed repetitive multifocal epileptiform discharges, which remained similar after administration of intravenous pyridoxine injection. Seizure recurred at the age of 3 months preceded by an episode of minor viral infection, which occurred multiple times per day. No significant change in seizure frequency was observed after 5-day oral pyridoxine trial, but subsequently, there was dramatic seizure improvement with oral pyridoxal-5′-phosphate (PLP). We hope to alert clinicians that in patients with neonatal epileptic encephalopathy, particularly with known KCNQ2 mutations, intravenous injection of pyridoxine (preferably with EEG monitoring), followed by both oral trial of pyridoxine and PLP should be considered. KCNQ2 mutations should also be considered in vitamin B6-responsive patients.

Objective This study explored factors which predict stroke survivors who could achieve “clinically significant functional gain” and return home when being discharged from a local hospital after in-patient stroke rehabilitation programme. Methods This study included 562 inpatients with stroke who were residing at community dwellings before onset of stroke, and transferred to a convalescent hospital for rehabilitation from four acute hospitals over one year. The main outcome variables of prediction were (a) achieving “clinically significant functional gain” as measured by (a1) achievement of “minimal clinically important difference” (MCID) of improvement in Functional Independence Measure Motor Measure (FIM-MM)”, (a2) one or more level(s) of improvement in function group according to the patients’ FIM-MM, and (b) discharge to home. Sixteen predictor variables were identified and studied firstly with univariate binary logistic regression and those significant variables were then put into multivariate binary logistic regression. Results Based on multivariate regression, the significant predictors for “clinically significant functional gain” were: younger age Conclusions This study identified findings consistent with overseas studies in additional to some new interesting findings. Early prediction of stroke discharge outcomes helps rehabilitation professionals and occupational therapists to focus on the use of appropriate intervention strategies and pre-discharge preparation.

Introduction: Valid assessments of quality of life (QoL) and cognition are important in caring for individuals with severe dementia; there is an urgent need for validated assessment tools for specific populations. This study aimed to develop and validate Chinese versions of the Quality of Life in Late-Stage Dementia (QUALID-C) scale and the Cognitive Test for Severe Dementia (CTSD-C) for Chinese older adults. Methods: This was a cross-sectional validation study comprised of 93 Chinese older adults with severe dementia recruited from 6 residential homes. The content and cultural validity of the QUALID-C and CTSD-C were evaluated by a 7-member expert panel, and interrater reliability, test-retest reliability, internal consistency, concurrent validity, and factorial structure were examined. Results: The QUALID-C showed acceptable internal consistency (Cronbach α = 0.65), good interrater reliability (intraclass correlation coefficient [ICC] = 0.99), and good test-retest reliability (ICC = 0.96). Principal component analysis yielded 3 factors; the items loaded on the factors were comparable to those in previous studies and suggested the scale’s multidimensionality to measure QoL. The CTSD-C showed satisfactory internal consistency (Cronbach α = 0.862), good interrater reliability (ICC = 0.99), and good test-retest reliability (ICC = 0.958). Principal component analysis yielded 3 factors; the items loaded on factors 1 and 2 resembled the items of the automatic response and attentional control factors of the original study. Conclusion: The QUALID-C and the CTSD-C are reliable and valid scales to measure the QoL and cognitive functions of Chinese older adults with severe dementia. These assessments can be utilized to evaluate the effectiveness of treatment and future research work.

Genomic changes observed across treatment may result from either clonal evolution or geographically disparate sampling of heterogeneous tumors. Here we use computational modeling based on analysis of fifteen primary breast tumors and find that apparent clonal change between two tumor samples can frequently be explained by pre-treatment heterogeneity, such that at least two regions are necessary to detect treatment-induced clonal shifts. To assess for clonal replacement, we devise a summary statistic based on whole-exome sequencing of a pre-treatment biopsy and multi-region sampling of the post-treatment surgical specimen and apply this measure to five breast tumors treated with neoadjuvant HER2-targeted therapy. Two tumors underwent clonal replacement with treatment, and mathematical modeling indicates these two tumors had resistant subclones prior to treatment and rates of resistance-related genomic changes that were substantially larger than previous estimates. Our results provide a needed framework to incorporate primary tumor heterogeneity in investigating the evolution of resistance., When examining the evolution of treatment resistance in breast cancer, perceived genomic changes may be due to clonal evolution or heterogeneous tumors. Here, the authors show that apparent clonal change can in fact be due to pre-treatment heterogeneity, and samples from at least two regions are necessary to detect treatment-induced clonal shifts

This study describes the study protocol of a manualized brief hope intervention that is based on the theoretical proposition - hope theory.Patients with stage 5 chronic kidney disease often had decisional regret when facing the tension of treatment alternatives between dialysis initiation and palliative care. Hope has been found to account for therapeutic changes in clients with depressive symptoms, heightens positive expectations, and striving to accomplish chosen goals. Nevertheless, little is known about the effect of hope on decisional conflict and its influences to the quality of life in these chronic kidney disease patients.This study is a single-blinded, randomized controlled trial.Participants will be recruited from a regional hospital (approved in April 2018). They will be randomly assigned in equal numbers to either the brief hope intervention or the control arm on completion of the baseline assessment on the possible need of dialysis initiation. Participants in the intervention group will receive the pre-dialysis education and a 4-week Brief Hope Intervention [consisting of four sessions at weekly intervals (two face-to-face sessions and two telephone follow-up sessions in between)], while those allocated to the control arm will receive the renal education and social chats. Outcome measures will be carried out prior to the intervention (baseline), immediately, and 1 month after the intervention. These consist of the hope level, decisional conflict, and quality of life. Healthcare resources use data will be reported.The study results have the potential to add scientific evidence to the research-tested programme when developing renal services integral to multimodal care management to optimize decision-making and attain better health outcomes.目的: 本研究描述了一个基于理论命题-希望理论的可操作性短期干预的研究方案。 背景: 慢性肾脏疾病5期患者在面对透析和姑息治疗较为紧张,因此,一般情况下,其都会后悔在这个过程中所作的决定。研究发现,希望可以对抑郁症患者的治疗产生影响,增强其积极的期望,致使其努力实现选定的目标。然而,人们并未充分了解希望在决策冲突中的作用以及其对慢性肾病患者生活质量的影响。 设计: 本研究为单盲、随机对照试验。 方法: 将从地区医院招募参与者(2018年4月获得批准)。如果已经完成透析用基线评估,所有参与者都将随机分配给短期希望干预组或对照组,且两组的人数相同。干预组的参与者接受透析前教育和为期4周的简短希望干预【包括每周4次的讨论(两次面对面讨论和两次电话随访)】,而控制组的参与者将接受肾脏知识教育,并将参与社交聊天。需要分别在干预前(基线)、干预时和干预后1个月对结果进行测量。具体内容包括希望水平、决策冲突和生活质量。此外,需要对医疗资源的使用数据进行报告。 影响: 本研究结果可能用作经研究验证的项目的科学证据,以便开发多种模式的肾脏护理及管理服务,最终优化决策并确保患者获得更好的健康结果。.

The most recent recommendations support learning of external cardiac massage (ECM) through feedback devices.The objective was to compare the effects on immediate and 3-month retention of ECM technical skills when using feedback devices compared with training without feedback as part of a half-day training session in medical students.This randomized study was performed using the Resusci Anne QCPR manikin in 64 medical students. We compared the quality of ECM with nonfeedback training in the control group (group 1) vs. 2 feedback learning methods (group 2, PocketCPR and group 3, Skill Reporter each used with visual display available to the trainee). At the end of the training session and 3 months later, students performed chest compressions blindly during a 2-min assessment session. The median compression score was the primary outcome for assessing immediate and long-term retention.Regarding immediate retention, the median compression score was significantly lower in group 1 (23%) than in groups 2 (81%) and 3 (72%) (p 0.05) with no difference between the 2 feedback methods. At 3 months, mean compression scores remained high but not significantly different between the 2 feedback groups.The use of a feedback device used for ECM training improves the quality of immediate retention of technical ECM skills compared with traditional teaching in medical students. At 3 months, the 2 groups with feedback retained a high level of performance. No significant difference could be demonstrated between the 2 feedback methods.

We report a new small peptide containing four amino acid residues (glycine-aspartic acid-proline-histidine) conjugated with palmitic acid (Palmitoyl-GDPH) that was synthesized, characterized and evaluated for its biological activities. The Palmitoyl-GDPH was prepared by solid phase peptide synthesis (SPPS) with high percentage purity of 98.6%. The results of circular dichroism (CD) demonstrated the feasibility and stability of Palmitoyl-GDPH secondary structure at many temperatures up to 60 °C. Palmitoyl-GDPH showed its greatest collagenase inhibition activity and nitric oxide (NO) scavenging effect of 80.00 ± 2.22% at 1.0 mg/ml and 83.40 ± 8.08% at 2.5 mg/ml, respectively. In addition, in-vitro cell based study revealed that Palmitoyl-GDPH was not toxic and possessed strong proliferative activity towards normal human dermal fibroblast (NHDF) cell line. Wound scratch assay method showed that Palmitoyl-GDPH significantly promoted the cell migration which progressed faster compared to tetracycline-treated group (positive control) by about 98.39 ± 2.79% and 95.79 ± 3.83%, respectively. Collectively, these results suggested that newly synthesized Palmitoyl-GDPH possessed a strong candidate for use as therapeutic agent and can be a novel approach in the treatment of cutaneous wounds.

Heart failure is the leading cause of morbidity and mortality worldwide. Standard treatment for heart failure includes pharmacotherapy and cardiac device implants. However, supportive approaches in managing dyspnea in heart failure are limited. This study aimed to test the efficacy of 20-minute mindful breathing in reducing dyspnea among patients admitted for acute decompensated heart failure. We conducted a parallel-group, non-blinded, randomized controlled trial of a single session of 20-minute mindful breathing plus standard care versus standard care alone among patients admitted for moderate to severe dyspnea due to acute decompensated heart failure, using the dyspnea score based on the Edmonton Symptom Assessment System (ESAS), at the Cardiology Unit of University Malaya Medical Centre in Malaysia. Thirty participants were randomly assigned to a single session of 20-minute mindful breathing plus standard care (n = 15) or standard care alone (n = 15), with no difference in their demographic and clinical characteristics. There was statistically significant reduction in dyspnea in the intervention group compared to the control group at minute 20 (U = 49.5, n1 = 15, n2 =15, median reduction in ESAS dyspnea score 1 = 2, median reduction in ESAS dyspnea score 2 = 0, mean rank 1 = 11.30, mean rank 2 = 19.70, z = −2.692, r = 0.4, P = 0.007). Our results provided evidence that a single session of 20-minute mindful breathing was efficacious in reducing dyspnea for patients admitted for acute decompensated heart failure.

TP53 gene mutations are very common in human cancer. While such mutations abrogate the tumor suppressive activities of the wild‐type (wt) p53 protein, some of them also endow the mutant (mut) protein with oncogenic gain of function (GOF), facilitating cancer progression. Yet, p53 may acquire altered functionality even without being mutated; in particular, experiments with cultured cells revealed that wtp53 can be rewired to adopt mut‐like features in response to growth factors or cancer‐mimicking genetic manipulations. To assess whether such rewiring also occurs in human tumors, we interrogated gene expression profiles and pathway deregulation patterns in the METABRIC breast cancer (BC) dataset as a function of TP53 gene mutation status. Harnessing the power of machine learning, we optimized a gene expression classifier for ER+Her2‐ patients that distinguishes tumors carrying TP53 mutations from those retaining wt TP53. Interestingly, a small subset of wt TP53 tumors displayed gene expression and pathway deregulation patterns markedly similar to those of TP53‐mutated tumors. Moreover, similar to TP53‐mutated tumors, these ‘pseudomutant’ cases displayed a signature for enhanced proliferation and had worse prognosis than typical wtp53 tumors. Notably, these tumors revealed upregulation of genes which, in BC cell lines, were reported to be positively regulated by p53 GOF mutants. Thus, such tumors may benefit from mut p53‐associated activities without having to accrue TP53 mutations., In ER+Her2‐ breast cancer (BC), p53 tumor suppressor gene mutations are associated with bad prognosis, relative to tumors that retain wild‐type (wt) p53. Applying machine learning to a large BC dataset reveals a subset of ER+Her2‐ tumors (pseudomutant p53 tumors) which, despite retaining wt p53, display gene expression and pathway deregulation profiles typical of p53‐mutated tumors, correlating with bad prognosis.

Aim Psychiatric comorbidity frequently occurs with at-risk mental state (ARMS) for psychosis. Its relationships with psychopathology, cognition and functioning, however, remain to be further clarified. We aimed to examine prevalence and correlates of psychiatric comorbidity, and its associations with psychosocial functioning and subjective quality-of-life (QoL) in a representative sample of Chinese ARMS individuals. Methods One hundred ten help-seeking participants aged 15 to 40 years with ARMS were recruited from a specialized early psychosis service in Hong Kong. ARMS status was verified by comprehensive assessment of at-risk mental state (CAARMS). Comorbid Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition non-psychotic psychiatric disorders at baseline were ascertained using diagnostic interview and medical record review. Assessments encompassing symptom profiles, psychosocial functioning, subjective QoL and a brief cognitive battery were conducted. Results Forty-nine (44.5%) ARMS participants were diagnosed as having comorbid non-psychotic psychiatric disorders at baseline, primarily depressive and anxiety disorders. Binary multiple logistic regression analysis revealed that female gender, more severe depressive symptoms, higher suicidality and poorer global cognitive functioning were independently associated with comorbid diagnosis status. ARMS participants with psychiatric comorbidity displayed significantly more limited extended social networks and poorer subjective QoL than those without psychiatric comorbidity. Conclusion Comorbid disorders were frequently observed in Chinese ARMS individuals, and were linked to poorer cognition and higher suicide risk. Our findings underscore a potential critical role of psychiatric comorbidity in determining social functioning and subjective QoL in at-risk individuals. Further longitudinal research is required to clarify trajectories of comorbid disorder status and its prospective impact on clinical and functional outcomes in ARMS populations.

E-hailing, which is also known as ride-hailing or ride-sourcing, has been on the rise across the globe. However, it is known as a disruptive innovation as unregulated services have triggered major disruptions and led to certain setbacks in the transportation industry. It has been blamed for the rise in privacy and safety issues, unfair business competition, and a decline in demand in the traditional taxi industry. In response to these issues, certain countries have started to regulate the e-hailing industry. The objective of this study is to identify, analyze, and contrast on the form and enforcement of Malaysian-Indonesian’s e-hailing regulation framework by using qualitative-comparative research. In this study, literature has been gathered from credible online sources. Based on the results of the study, there are commonalities and differences between the Malaysian and Indonesian’s e-hailing regulation framework. Furthermore, the implications of the study have been discussed. For instance, the current state of the e-hailing industry is underregulated rather than unregulated. Policy makers should seek to improve existing regulation framework rather than starting new regulations from ground up to minimize the risk of overregulation that might eventually diminish the industry.

Triple-negative breast cancer (TNBC) accounts for 10 to 20% of breast cancer, with chemotherapy as its mainstay of treatment due to lack of well-defined targets, and recent genomic sequencing studies have revealed a paucity of TNBC-specific mutations. Recurrent gene fusions comprise a class of viable genetic targets in solid tumors; however, their role in breast cancer remains underappreciated due to the complexity of genomic rearrangements in this cancer. Our interrogation of the whole-genome sequencing data for 215 breast tumors catalogued 99 recurrent gene fusions, 57% of which are cryptic adjacent gene rearrangements (AGRs). The most frequent AGRs, BCL2L14–ETV6 , TTC6–MIPOL1 , ESR1–CCDC170 , and AKAP8–BRD4 , were preferentially found in the more aggressive forms of breast cancers that lack well-defined genetic targets. Among these, BCL2L14–ETV6 was exclusively detected in TNBC, and interrogation of four independent patient cohorts detected BCL2L14–ETV6 in 4.4 to 12.2% of TNBC tumors. Interestingly, these fusion-positive tumors exhibit more aggressive histopathological features, such as gross necrosis and high tumor grade. Amid TNBC subtypes, BCL2L14–ETV6 is most frequently detected in the mesenchymal entity, accounting for ∼19% of these tumors. Ectopic expression of BCL2L14 – ETV6 fusions induce distinct expression changes from wild-type ETV6 and enhance cell motility and invasiveness of TNBC and benign breast epithelial cells. Furthermore, BCL2L14 – ETV6 fusions prime partial epithelial – mesenchymal transition and endow resistance to paclitaxel treatment. Together, these data reveal AGRs as a class of underexplored genetic aberrations that could be pathological in breast cancer, and identify BCL2L14–ETV6 as a recurrent gene fusion in more aggressive form of TNBC tumors.

Invasive lobular carcinoma (ILC) is the second most common type of breast cancer after invasive ductal carcinoma (IDC), accounting for approximately 10-15% of all breast tumors. ILC is characterized by inactivation of E-Cadherin and neoplastic cells that invade the stroma in a "single-file" pattern. Women with ILC are usually older, have used hormone replacement therapy and are more likely to have hormone receptor-positive disease. ILCs have similar survival to IDCs at both five and 10 years, but despite this, the clinical course is distinct: ILCs are three times more likely to metastasize to the peritoneum, gastrointestinal tract, and ovaries and are more frequently bilateral. Therefore, tailored therapeutic options for this distinct, hard-to-treat subtype of breast cancer are required. As part of the RATHER FP7 HEALTH consortium (www.ratherproject.com), we carried out RNA-Seq analysis of 61 primary ILC samples and identified that high expression of the BET family protein Brd3 (uniquely among BRD family members) was associated with poor recurrence free survival (p=0.03, HR 8.63, CI 1.22-60.85). This observation was further validated in the independent METABRIC cohort (n=99), where again, high Brd3 expression (and not other BRD members) was associated with poor recurrence-free survival (p Citation Format: Darran P O'Connor, Louise Walsh, Kathryn Haley, Bruce Moran, Brian Mooney, Stephen Madden, Sudipto Das, Oscar Rueda, Catriona Dowling, Damir Vareslija, Suet-Feung Chin, Sabine Linn, Leonie Young, Karin Jirstrom, John P Crown, Rene Bernards, Carlos Caldas, William M Gallagher, Triona Ni Chonghaile. Combination of BET and FGFR inhibition as a rational therapeutic strategy for invasive lobular breast cancer [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P3-10-06.

Background Ramucirumab-an IgG1 vascular endothelial growth factor receptor 2 antagonistplus docetaxel was previously reported to improve progression-free survival in platinum-refractory, advanced urothelial carcinoma. Here, we report the secondary endpoint of overall survival results for the RANGE trial.Methods We did a randomised, double-blind, phase 3 trial in patients with advanced or metastatic urothelial carcinoma who progressed during or after platinum-based chemotherapy. Patients were enrolled from 124 investigative sites (hospitals, clinics, and academic centres) in 23 countries. Previous treatment with one immune checkpoint inhibitor was permitted. Patients were randomly assigned (1:1) using an interactive web response system to receive intravenous ramucirumab 10 mg/kg or placebo 10 mg/kg volume equivalent followed by intravenous docetaxel 75 mg/m 2 (60 mg/m 2 in Korea, Taiwan, and Japan) on day 1 of a 21-day cycle. Treatment continued until disease progression, unacceptable toxicity, or other discontinuation criteria were met. Randomisation was stratified by geographical region, Eastern Cooperative Oncology Group performance status at baseline, and visceral metastasis. Progression-free survival (the primary endpoint) and overall survival (a key secondary endpoint) were assessed in the intention-to-treat population. The study is registered with ClinicalTrials.gov, NCT02426125; patient enrolment is complete and the last patient on treatment is being followed up for safety issues.Findings Between July 20, 2015, and April 4, 2017, 530 patients were randomly allocated to ramucirumab plus docetaxel (n=263) or placebo plus docetaxel (n=267) and comprised the intention-to-treat population. At database lock (March 21, 2018) for the final overall survival analysis, median follow-up was 7.4 months (IQR 3.5-13.9). In our sensitivity analysis of investigator-assessed progression-free survival at the overall survival database lock, median progression-free survival remained significantly improved with ramucirumab compared with placebo (4.1 months [95% CI 3.3-4.8] vs 2.8 months [2.6-2.9]; HR 0.696 [95% CI 0.573-0.845]; p=0.0002). Median overall survival was 9.4 months (95% CI 7.9-11.4) in the ramucirumab group versus 7.9 months (7.0-9.3) in the placebo group (stratified HR 0.887 [95% CI 0.724-1.086]; p=0.25). Grade 3 or worse treatment-related treatment-emergent adverse events in 5% or more of patients and with an incidence more than 2% higher with ramucirumab than with placebo were febrile neutropenia (24 [9%] of 258 patients in the ramucirumab group vs 16 [6%] of 265 patients in the placebo group) and neutropenia (17 [7%] of 258 vs six [2%] of 265). Serious adverse events were similar between groups (112 [43%] of 258 patients in the ramucirumab group vs 107 [40%] of 265 patients in the placebo group). Adverse events related to study treatment and leading to death occurred in eight (3%) patients in the ramucirumab group versus five (2%) patients in the placebo group.Interpretation Additional follow-up supports that ramucirumab plus docetaxel significantly improves progression-free survival, without a significant improvement in overall survival, for patients with platinum-refractory advanced urothelial carcinoma. Clinically meaningful benefit might be restricted in an unselected population. Copyright (C) 2019 Elsevier Ltd. All rights reserved.

Despite the official statistics showing that the number of drug users has been declining, the problem of drug abuse remains serious in Hong Kong. This problem is evidenced by the trend of hidden and prolonged drug abuse. The recovery of drug abusers is an important process, because the misuse of drugs can cause many bio-psycho-social complications. Therefore, 11 Counselling Centres for Psychotropic Substance Abusers (CCPSAs) in different districts in Hong Kong play an important role on those drug abusers [1]. As a core community-based drug rehabilitation service in Hong Kong, studies about CCPSAs are limited. This study uses a descriptive qualitative approach to explore the experience of drug abusers participating in community-based drug rehabilitation services provided by CCPSAs. Five CCPSA users, who utilized the services for more than two months, participated in the semi-structured face-to-face interviews. Data collected were then analysed by thematic analysis, and five themes were generated: 1) receiving supportive counselling service in CCPSAs, 2) revealing variance towards nonmandatory services in CCPSAs, 3) encountering intrapersonal conflicts when participating in CCPSAs, 4) expanding social network through integration in group activities and 5) wishing to be a companion to other drug abusers. Findings of this study provide valuable insights towards services modification and the enhancement of drug rehabilitation and drug abusers’ wellbeing over the collaboration of healthcare workers, services providers and the media. However, this study has some limitations, and it presents suggestions for future research.

Rare protein-truncating variants (PTVs) in PALB2 confer increased risk to breast cancer, but relatively few studies have reported the characteristics of tumours with PALB2 PTVs. In this study, we describe molecular characteristics of tumours with either germline or somatic alterations in PALB2. DNA from fresh frozen tumour tissues and matched peripheral blood lymphocytes for 560 breast cancer patients was subjected for whole-exome sequencing (WES), and RNA from tumour tissues was subjected to RNA sequencing (RNA-seq). We found six cases with germline and three with somatic protein-truncating variants in PALB2. The characteristics of tumours in patients with PALB2 PTVs were similar to those with BRCA1 and BRCA2 PTVs, having significantly more somatic alterations, and a high proportion of the mutational signature and genomic scar scores characteristic of deficiencies in homologous recombination (HR), compared to tumours arising in non-carriers. Unlike tumours arising in patients with BRCA1 and BRCA2 PTVs, PALB2 tumours did not have high prevalence of TP53 somatic alterations or an enriched immune microenvironment. In summary, PALB2 tumours show the homologous recombination deficiencies characteristic of BRCA1 and BRCA2 tumours, and highlight the potential clinical relevance of PALB2 mutational status in guiding therapeutic choices.