HTA community perspectives on the use of patient preference information: lessons learned from a survey with members of HTA bodies.

This research sought to assess whether and how patient preference (PP) data are currently used within health technology assessment (HTA) bodies and affiliated organizations involved in technology/drug appraisals and assessments. An exploratory survey was developed by the PP Project Subcommittee of the HTA International Patient and Citizen Involvement Interest Group to gain insight into the use, impact, and role of PP data in HTA, as well as the perceived barriers to its incorporation. Forty members of HTA bodies and affiliated organizations from twelve countries completed the online survey. PP data were reported to be formally considered as part of the HTA evidence review process by 82.5 percent of the respondents, while 39.4 percent reported that most of the appraisals and assessments within their organization in the past year had submitted PP data. The leading reason for why PP data were not submitted in most assessments was time/resource constraints followed by lack of clarity on PP data impact. Participants reported that PP data had a moderate level of influence on the deliberative process and outcome of the decision, but a higher level of influence on the decision's quality. Most (81.8 percent) felt patient advocacy groups should be primarily responsible for generating and submitting this type of evidence. Insights from the survey confirm the use of PP data in HTA but reveal barriers to its broader and more meaningful integration. Encouragingly, participants believe obstacles can be overcome, paving the way for a second phase of research involving in-depth collaborative workshops with HTA representatives.

MUC1-C oncoprotein induces TCF7L2 transcription factor activation and promotes cyclin D1 expression in human breast cancer cells.

MUC1 is a heterodimeric glycoprotein that is overexpressed in breast cancers. The present studies demonstrate that the oncogenic MUC1 C-terminal subunit (MUC1-C) associates with the TCF7L2 transcription factor. The MUC1-C cytoplasmic domain (MUC1-CD) binds directly to the TCF7L2 C-terminal region. MUC1-C blocks the interaction between TCF7L2 and the C-terminal-binding protein (CtBP), a suppressor of TCF7L2-mediated transcription. TCF7L2 and MUC1-C form a complex on the cyclin D1 gene promoter and MUC1-C promotes TCF7L2-mediated transcription by the recruitment of ß-catenin and p300. Silencing MUC1-C in human breast cancer cells down-regulated activation of the cyclin D1 promoter and decreased cyclin D1 expression. In addition, a MUC1-C inhibitor blocked the interaction with TCF7L2 and suppressed cyclin D1 levels. These findings indicate that the MUC1-C oncoprotein contributes to TCF7L2 activation and thereby promotes cyclin D1 expression in breast cancer cells.

MUC1-C oncoprotein confers androgen-independent growth of human prostate cancer cells.

BACKGROUND: The mucin 1 (MUC1) heterodimeric oncoprotein is overexpressed in human prostate cancers with aggressive pathologic and clinical features. However, few insights are available regarding the functional role of MUC1 in prostate cancer. METHODS: Effects of MUC1-C on androgen receptor (AR) expression were determined by RT-PCR, immunoblotting and AR promoter activation. Coimmunoprecipitations, direct binding assays, and chromatin immunoprecipitation (ChIP) studies were performed to assess the interaction between MUC1-C and AR. Cells were analyzed for invasion, growth in androgen-depleted medium, and sensitivity to MUC1-C inhibitors. RESULTS: The present studies in androgen-dependent LNCaP and LAPC4 prostate cancer cells demonstrate that the oncogenic MUC1-C subunit suppresses AR expression. The results show that MUC1-C activates a posttranscriptional mechanism involving miR-135b-mediated downregulation of AR mRNA levels. The results further demonstrate that MUC1-C forms a complex with AR through a direct interaction between the MUC1-C cytoplasmic domain and the AR DNA-binding domain (DBD). In addition, MUC1-C associates with AR in a complex that occupies the PSA promoter. The interaction between MUC1-C and AR is associated with induction of the epithelial-mesenchymal transition (EMT) and increased invasion. MUC1-C also conferred growth in androgen-depleted medium and resistance to bicalutamide treatment. Moreover, expression of MUC1-C resulted in sensitivity to the MUC1-C inhibitor GO-203 with inhibition of growth in vitro. GO-203 treatment also inhibited growth of established tumor xenografts in nude mice. CONCLUSIONS: These findings indicate that MUC1-C suppresses AR expression in prostate cancer cells and confers a more aggressive androgen-independent phenotype that is sensitive to MUC1-C inhibition.

Androgen receptor regulates expression of the MUC1-C oncoprotein in human prostate cancer cells.

BACKGROUND: The MUC1 heterodimeric oncoprotein is aberrantly overexpressed in human prostate cancers with more aggressive pathologic and clinical features. However, the signals that regulate MUC1 expression in prostate cancer cells are not well understood. METHODS: MUC1 expression was studied in androgen-dependent and -independent prostate cancer cell lines by quantitative RT-PCR, immunoblotting and assessment of MUC1 promoter activation. Chromatin immunoprecipitation (ChIP) studies were performed to assess androgen receptor (AR) occupancy on the MUC1 promoter. Post-transcriptional regulation of MUC1 expression was assessed by miR-125b-mediated effects on activity of the MUC1 3' untranslated region (3'UTR). RESULTS: The present studies demonstrate that AR occupies a consensus AR element on the MUC1 promoter in androgen-dependent LNCaP, but not in androgen-independent DU145 and PC3, prostate cancer cells. The results further show that AR downregulates MUC1 gene transcription. Stable introduction of exogenous AR in PC3 (PC3/AR) cells and then silencing of AR confirmed AR-mediated repression of the MUC1 promoter. AR signaling has also been shown to drive miR-125b expression. The present studies further demonstrate that miR-125b suppresses MUC1 translation in LNCaP cells and that an anti-sense miR-125b upregulates expression of MUC1 protein. In addition, stable expression of miR-125b in DU145 cells resulted in decreases in MUC1 levels. CONCLUSIONS: These findings demonstrate that AR signaling regulates MUC1 expression by transcriptional and posttranscriptional mechanisms in prostate cancer cells.

Current updates on adaptive immune response by B cell and T cell stimulation and therapeutic strategies for novel coronavirus disease 2019 (COVID-19) treatment.

The prevalence of COVID-19 continues to rise with more than 114,315,846 million confirmed cases and 2,539,427 deaths worldwide by 3 March 2021 and this number kept on increasing day by day. There is no clear therapeutic treatment or vaccine available for COVID-19 till date and by seeing such a high rise in the cases of COVID-19 on daily basis, it would have been necessary to implement precautions and hygienic measures to monitor and reduce human-to-human transmission of SARS-CoV-2 before there is any successful intervention/treatment available. Currently, several studies demonstrated the important improvements in both the innate and adaptive immune systems of COVID-19 patients. In particular, pre-existing research, on immune response to B cell and T cells are highlighting that pre-existing immunity exists in about 90% of the general population because of previous exposure to CoVs and having immunity against these CoVs. Although it is not clear from, the current studies on COVID-19 but it assumed that, it might have implication to COVID-19 severity and could play an important role in treatment or vaccine development against COVID-19. This review summarizes the information from occurrence of SARS-CoV-2 to its pathogenesis, transmission, adaptive immune response with respect to T cell and B cell stimulation and therapeutic interventions/treatment against COVID-19.

PKG Movement Recording System Use Shows Promise in Routine Clinical Care of Patients With Parkinson's Disease.

Parkinson's disease (PD) is a debilitating, neurodegenerative disorder that affects nearly one million people. It's hallmark signs and symptoms include slow movements, rigidity, tremor, and unstable posture. Additionally, non-motor symptoms such as sleeplessness, depression, cognitive impairment, impulse control behaviors (ICB) have been reported. Today, treatment regimens to modify disease progression do not exist and as such, treatment is focused on symptom relief. Additionally, physicians are challenged to base their diagnoses and treatment plans on unreliable self-reported symptoms, even when used in conjunction to validated assessments such as the Unified Parkinson's Disease Rating Scale (UPDRS) and clinical exams. Wearable technology may provide clinicians objective measures of motor problems to supplement current subjective methods. Global Kinetics Corporation (GKC) has developed a watch-device called the Personal KinetiGraph (PKG) that records movements and provides patients medication dosing reminders. A separate clinician-use report supplies longitudinal motor and event data. The PKG was FDA-cleared in September 2016. We studied 63 PD patients during 85 routine care visits in 2 US academic institutions, evaluating the clinical utility of the PKG. Patients wore a PKG for 6 continuous days before their visit. Next, PKG data was uploaded to produce a report. In clinic, physicians discussed PD symptoms with patients and conducted a motor examination prior to reviewing the PKG report and comparing it to their initial assessments. Lastly, patient, caregiver and physician satisfaction surveys were conducted by each user. Across all visits when patients did not report bradykinesia or dyskinesia, the PKG reported these symptoms (50 and 33% of the time, respectively). The PKG provided insights for treatment plans in 50 (79%) patients across 71 (84%) visits. Physicians found improved patient dialogue in 50 (59%) visits, improved ability to assess treatment impact in 32 (38%) visits, and improved motor assessment in 28 (33%) visits. Patients stated in 82% of responses that they agreed or strongly agreed in PKG training, usability, performance, and satisfaction. In 39% of responses, they also reported a very valuable impact on their care. PKG use in 63 PD patients within our clinical practice showed clinically relevant utility in many areas.

Role of urodynamics in stress urinary incontinence: A critical appraisal.

INTRODUCTION: Role of urodynamics prior to surgery of stress urinary incontinence (SUI) is under constant debate. Demonstration of the presence of detrusor overactivity is the only aspect that has been emphasized in the literature so far. We believe that there are number of other factors which may influence the evaluation and in turn the choice of surgical management and prediction of outcome of treatment. They are as follows: (1) Presence of voiding inefficiency, (2) asymptomatic detrusor overactivity, (3) and severity of SUI. These features may complicate the precise evaluation of patients of SUI. The main objective of this study is to analyze the dynamics of leakage and voiding using urodynamics. This study also aims at correlating these findings with clinical information. MATERIALS AND METHODS: One hundred consecutive cases referred to our center for preoperative evaluation of SUI were recruited in the study prospectively. All patients were interrogated using International Consultation on Incontinence Questionnaire. All patients underwent complete urodynamic evaluation including uroflowmetry, filling cystometry, leak point pressure measurement, and pressure flow studies, according to Good Urodynamic Practice guidelines. Patients' symptoms were correlated with urodynamic findings, with special emphasis on the presence of detrusor overactivity, severity of SUI, voiding efficiency, and presence of bladder outlet obstruction. Clinical information and urodynamic findings were correlated using Chi-square test. RESULTS: There is a statistically significant correlation between the presence of symptoms of urge urinary incontinence and urodynamic findings of detrusor overactivity at P < 0.05. There is a statistically significant correlation between the symptoms of urge incontinence (in addition to SUI) and urodynamic findings of intrinsic sphincter deficiency at P < 0.05. Fifteen of 51 patients who did not have associated storage symptoms were found to have some degree of detrusor overactivity on urodynamic evaluation. There was no statistically significant correlation between asymptomatic cases of urge incontinence and incidental finding of detrusor overactivity at P < 0.05. There is no statistically significant correlation between the urodynamic findings of symptoms of voiding dysfunction and urodynamic findings, suggestive of the same value at P < 0.05. CONCLUSIONS: Urodynamic study in SUI has a potential of giving much more information than demonstration of Detrusor Overactivity alone. The predominant symptom of urge urinary incontinence can predictably diagnose detrusor overactivity in these cases. However, the incidence of asymptomatic detrusor overactivity remains as high as 15% and may have implication in postoperative results. This study clearly shows that there is a definite incidence of significant voiding dysfunction, which cannot be reliably evaluated without properly conducted pressure flow study. This factor may govern the choice of correct treatment which also predicts the outcome more reliably. Preoperative urodynamic study thus adds a dimension of precision to evaluation of the patients of SUI and may also influence technique and outcome measures in this group of patients.

Bladder outlet obstruction in women.

Bladder outlet obstruction in females remains a poorly understood condition and is much rarer as compared to males. More difficult is the objective diagnosis of this condition. There is no general agreement on the Urodynamic parameters to define the condition with certainty. A number of conditions are involved particularly in urinary retention in females are not completely understood. Besides, external sphincter dysfunction and post surgical retentions add another group of conditions which are distinct from retentions seen in the males. This article takes a review of various aetiological factors of Bladder outlet obstruction in women. An attempt is made to standardise the Urodynamic parameters for use in females, based on our data and experimentation on the models of the bladder and urethra. This article also takes a review of uncommon conditions such as Fowler's syndrome which often complicate evaluation of this condition.

MUC1-C oncoprotein promotes STAT3 activation in an autoinductive regulatory loop.

Signal transducer and activator of transcription 3 (STAT3) is activated in human breast cancer and other malignancies. Mucin 1 (MUC1) is a heterodimeric cell surface glycoprotein that is overexpressed in human carcinomas and, like STAT3, promotes cell survival and induces transformation. We found that in breast cancer cells, the MUC1 carboxyl-terminal receptor subunit (MUC1-C) associates with the gp130-Janus-activated kinase 1 (JAK1)-STAT3 complex. The MUC1-C cytoplasmic domain interacted directly with JAK1 and STAT3, and MUC1-C was necessary for JAK1-mediated STAT3 activation. In turn, MUC1-C and activated STAT3 occupied the promoter of MUC1, and MUC1-C contributed to STAT3-mediated activation of MUC1 transcription. The MUC1-C inhibitor GO-201 blocked the MUC1-C interaction with STAT3, thereby decreasing MUC1-C and STAT3 occupancy on the MUC1 and STAT3 promoters and activation of STAT3 target genes, including MUC1 itself. These findings indicate that MUC1-C promotes STAT3 activation and that MUC1-C and STAT3 function in an autoinductive loop that may play a role in cancer cell survival.

MUCIN 1 ONCOPROTEIN EXPRESSION IS SUPPRESSED BY THE miR-125b ONCOMIR.

The MUC1 oncoprotein is overexpressed in most human breast cancers by mechanisms that are incompletely understood. The microRNA, miR-125b, is downregulated in breast cancer cells. The present studies demonstrate that the MUC1 3'UTR contains a site for binding of the miR-125b seed region. The results show that the MUC1 3'UTR suppresses luciferase expression and that this effect is abrogated by mutation or deletion of the miR-125b binding site. Expression of an anti-sense miR-125b in BT-549 breast cancer cells was associated with induction of MUC1 protein, but not MUC1 mRNA, levels. The anti-sense miR-125b also increased BT-549 cell growth by a MUC1-dependent mechanism. In addition, overexpression of exogenous miR-125b downregulated MUC1 protein, and not MUC1 transcripts, in ZR-75-1 breast cancer cells. Silencing of MUC1 in ZR-75-1 cells with a siRNA has been shown to promote DNA damage-induced apoptosis. In concert with these observations, miR-125b-induced decreases in MUC1 levels increased the apoptotic response of ZR-75-1 cells to cisplatin treatment. These findings indicate that miR-125b suppresses translation of the MUC1 oncoprotein and that miR-125b thereby functions as a tumor suppressor in breast cancer cells.

MUC1-C oncoprotein functions as a direct activator of the nuclear factor-kappaB p65 transcription factor.

Nuclear factor-kappaB (NF-kappaB) is constitutively activated in diverse human malignancies. The mucin 1 (MUC1) oncoprotein is overexpressed in human carcinomas and, like NF-kappaB, blocks cell death and induces transformation. The present studies show that MUC1 constitutively associates with NF-kappaB p65 in carcinoma cells. The MUC1 COOH-terminal subunit (MUC1-C) cytoplasmic domain binds directly to NF-kappaB p65 and, importantly, blocks the interaction between NF-kappaB p65 and its inhibitor IkappaBalpha. We show that NF-kappaB p65 and MUC1-C constitutively occupy the promoter of the Bcl-xL gene in carcinoma cells and that MUC1-C contributes to NF-kappaB-mediated transcriptional activation. Studies in nonmalignant epithelial cells show that MUC1-C interacts with NF-kappaB in the response to tumor necrosis factor-alpha stimulation. Moreover, tumor necrosis factor-alpha induces the recruitment of NF-kappaB p65-MUC1-C complexes to NF-kappaB target genes, including the promoter of the MUC1 gene itself. We also show that an inhibitor of MUC1-C oligomerization blocks the interaction with NF-kappaB p65 in vitro and in cells. The MUC1-C inhibitor decreases MUC1-C and NF-kappaB p65 promoter occupancy and expression of NF-kappaB target genes. These findings indicate that MUC1-C is a direct activator of NF-kappaB p65 and that an inhibitor of MUC1 function is effective in blocking activation of the NF-kappaB pathway.

MUC1 oncoprotein is a druggable target in human prostate cancer cells.

Human prostate cancers are dependent on the androgen receptor for their progression. The MUC1 heterodimeric oncoprotein is aberrantly overexpressed in prostate cancers; however, it is not known if MUC1 is of functional importance to these tumors. To assess dependence on MUC1, we synthesized an inhibitor, designated GO-201, which interacts directly with the MUC1-C subunit at its oligomerization domain. Treatment of MUC1-positive DU145 and PC3 prostate cancer cells with GO-201, and not an altered version, resulted in inhibition of proliferation. GO-201 also induced necrotic cell death that was associated with increases in reactive oxygen species, loss of mitochondrial transmembrane potential, and depletion of ATP. By contrast, GO-201 had no effect against MUC1-negative LNCaP, CWR22Rv1, and MDA-PCa-2b prostate cancer cells. Significantly, GO-201 treatment of DU145 and PC3 xenografts growing in nude mice resulted in complete tumor regression and prolonged lack of recurrence. These findings indicate that certain prostate cancer cells are dependent on MUC1-C for growth and survival and that directly targeting MUC1-C results in their death in vitro and in tumor models.

Direct targeting of the mucin 1 oncoprotein blocks survival and tumorigenicity of human breast carcinoma cells.

The mucin 1 (MUC1) oncoprotein is aberrantly overexpressed by approximately 90% of human breast cancers. However, there are no effective agents that directly inhibit MUC1 and induce death of breast cancer cells. We have synthesized a MUC1 inhibitor (called GO-201) that binds to the MUC1 cytoplasmic domain and blocks the formation of MUC1 oligomers in cells. GO-201, and not an altered version, attenuates targeting of MUC1 to the nucleus of human breast cancer cells, disrupts redox balance, and activates the DNA damage response. GO-201 also arrests growth and induces necrotic death. By contrast, the MUC1 inhibitor has no effect on cells null for MUC1 expression or nonmalignant mammary epithelial cells. Administration of GO-201 to nude mice bearing human breast tumor xenografts was associated with loss of tumorigenicity and extensive necrosis, which results in prolonged regression of tumor growth. These findings show that targeting the MUC1 oncoprotein is effective in inducing death of human breast cancer cells in vitro and in tumor models.

Synthesis and in vivo antihyperglycemic activity of nature-mimicking furanyl-2-pyranones in STZ-S model.

Various nature-mimicking pyranones such as 6-(2,5-dimethylfuran-3-yl)-pyran-2-one and 6-(furan-2-yl)-pyran-2-one derivatives were synthesized and evaluated for their in vivo antihyperglycemic activity in sucrose-loaded streptozotocin-induced diabetic rat model. Five of the test compounds showed significant lowering of plasma glucose level in STZ-S model.