Steroids and growth factors control neuronal development through their receptors under physiological and pathological conditions. We show that PC12 cells harbor endogenous androgen receptor (AR), ...whose inhibition or silencing strongly interferes with neuritogenesis stimulated by the nonaromatizable synthetic androgen R1881 or NGF. This implies a role for AR not only in androgen signaling, but also in NGF signaling. In turn, a pharmacological TrkA inhibitor interferes with NGF- or androgen-induced neuritogenesis. In addition, androgen or NGF triggers AR association with TrkA, TrkA interaction with PI3-K δ, and downstream activation of PI3-K δ and Rac in PC12 cells. Once associated with AR, filamin A (FlnA) contributes to androgen or NGF neuritogenesis, likely through its interaction with signaling effectors, such as Rac. This study thus identifies a previously unrecognized reciprocal cross-talk between AR and TrkA, which is controlled by β1 integrin. The contribution of FlnA/AR complex and PI3-K δ to neuronal differentiation by androgens and NGF is also novel. This is the first description of AR function in PC12 cells.
Kebutuhan yang semakin meningkat akan banyaknya data yang dikirim dan kecepatan pengiriman data melalui teknologi wireless mengakibatkan tingginya minat terhadap perangkat dengan Bandwidth lebar. ...Memperbaiki desain antena adalah salah satu cara untuk meningkatkan Bandwidth. Antena didesain sedemikian rupa agar mendapatkan parameter antena yang bernilai efektif salah satunya untuk meningkatkan bandwidth antena. Salah satu teknik yang digunakan untuk memperbaiki parameter antena miksrostrip yaitu teknik Defect Ground Structure (DGS) dengan metode yang digunakan adalah perhitungan, simulasi dan pengujian. Hasil pengujian antena mikrostrip array semicircular tanpa DGS diperoleh nilai parameter return loss sebesar -13,7 dB dan nilai VSWR sebesar 1,518 serta memiliki gain bernilai 1,3 dBi pada frekuensi 2455 MHz. Antena ini memiliki bentuk pola radiasi bidirectional. Bandwidth antena yang diperoleh sebesar 14 MHz. Hasil pengujian antena mikrostrip array semicircular dengan DGS diperoleh nilai parameter return loss sebesar -14,4 dB dan nilai VSWR sebesar 1,469 serta memiliki gain bernilai 2,8 dBi pada frekuensi 2455 MHz. Antena ini memiliki bentuk pola radiasi directional. Bandwidth antena yang diperoleh sebesar 10 MHz. Kesimpulan dari penelitian ini adalah antena mikrostrip array semicircular tanpa DGS mempunyai bandwidth yang lebih kecil dibandingkan dengan antena mikrostrip array semicircular dengan DGS yaitu dengan selisih sebesar 3,5 MHz.
Summary
Targeted therapy for chronic myeloid leukaemia (CML) has allowed for a near‐normal patient life‐expectancy; however, quality of life and aggravation of existing co‐morbidities have posed new ...treatment challenges. In clinical practice, TKI dose reduction occurs frequently, often on multiple occasions, because of intolerance. We conducted a retrospective ‘real‐world practice’ review of 246 patients receiving lower than standard dose (LD) TKI after the achievement of major molecular response (MR3), because of intolerable adverse events. In 274 of 298 cases of dose reduction (91·9%), MR3 was maintained at median follow‐up of 27·3 months. One patient progressed to blast crisis while on LD TKI. Two patients developed two new ABL kinase domain mutations (T315I and V299L), of whom one had achieved deep molecular response on an alternative LD TKI at last follow‐up. Seventy‐six patients eventually discontinued LD TKI and the two‐year treatment‐free remission (TFR) rate in these patients was 74·1%. The majority of patients with CML in at least MR3 appear to be safely managed with LD TKI, although three of 246 patients had new events (progression and new mutation), indicating that this approach requires vigilance. TKI LD does not prevent the achievement of TFR in this patient population.
Advancements in the management of patients with chronic myeloid leukemia (CML) allowed them to achieve survival comparable with their healthy counterparts. Consequently, their care has widened with ...growing focus on quality of life, including parenting children. Although tyrosine kinase inhibitors (TKI) are contraindicated in pregnancy given their teratogenic effect, their effect on male fertility is less clear with contradictory results from animal studies and case reports/series. We compared the sperm analysis parameters, as the gold-standard assessment for male fertility, of 11 patients with CP- CML before and after TKI therapy. Median therapy duration was 5.1 years (range: 2.5-16.5). The sperm concentration, % progressive, and total motility before and after therapy were not significantly different (
= 0.376, 0.569, and 0.595, respectively). Our results suggest no impairment in fertility potential in male patients after TKI therapy. A larger sample size is crucial to support/refute our findings.
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Background:
The new SARS-CoV-2-induced disease (COVID-19) pandemic has represented a huge challenge for the health systems and has been responsible for almost 700.000 deaths worldwide as of 1st ...August 2020. Older age, male sex, comorbidities, ethnicity and socioeconomic factorsare risk factors for severe COVID-19. While the direct effect of solid cancer on the COVID-19 outcome has been investigated and is still debated, limited information is available on the impact of an underlying hematological malignancy on the risk of contracting SARS-CoV-2, the clinical presentation and the outcome of the infection.
We report on the prevalence of SARS-CoV-2 infection in a large cohort of patients (pts) with chronic myeloid leukemia (CML).
Methods:
We retrospectively investigated the exposure to SARS-CoV-2 through serological testing in a single centre cohort of CML pts. Of more than 600 pts on active follow-up, we have screened 161 pts between 1st June and 27th July 2020. At each consultation, we recorded any exposure to or symptoms of SARS-CoV-2 infection in the preceding 6 months.
The Imperial Hybrid DABA, a two-step double antigen binding assay (DABA) for the detection and measurement of total antibody directed to the receptor binding domain (RBD) of SARS-CoV-2 was used for analysis. The cut-off (CO) for positivity is established by adding 0.1 to the average of optical density (OD) obtained for the negative controls. A sample-OD/cut-off (S/CO) value ≥ 1 is considered reactive.
Results:
161 CML pts in chronic phase underwent serological testing (median age 54 years (18-92), male n=94). Twenty pts were off TKI (post-alloSCT, n=12; in treatment free remission n=6; pregnancy=1 and intolerance n=1) and 141 were on active treatment (imatinib n=41, dasatinib n=38, nilotinib n=23, bosutinib n=21, asciminib n=11, ponatinib n=6 and K0706 n=1). The ethnic distribution was White (n=119), Asian-Indian (n= 24), Asian-Chinese (n=3), Black (n=9), Arab (n=5), Mixed Asian-White (n=1).
Eighteen pts (11.2%) have tested positive (Table 1). Thirty-eight pts (23.6%) reported symptoms compatible with COVID-19 of whom 12 (31.6%) were DABA positive. Six of 123 (4.9%) asymptomatic pts also tested positive. The time from onset of symptoms to the date of testing were similar in both seropositive (105 days, range 56-180) and seronegative pts (100 days, range 21-205). The median S/CO ratio was 9.9 (1-23.3) in the symptomatic and 1.5 (1.2-21.4) in the asymptomatic pts.
Among the 18 positive pts, the median age at symptom presentation was 54 years (38-75) and 12 were males. The median time from CML diagnosis was 7.6 years (0.2-20) and two pts were post-alloSCT. Ethnicity was White, Asian-Indian, Black in 8 (44.4%), 6 (33%) and 4 (22.2%), respectively.
In 15 pts (83.3%) symptoms were absent or mild, moderate in 2 and severe in one patient 2 years post-alloSCT on continuing immunosuppression for GvHD. Only 2/18 had PCR tests for SARS-CoV-2 at the time of infection and both were positive. Of the 16 pts not tested for antigen, 2 had been in close contact with a family member with a PCR-confirmed SARS-CoV-2 infection. In the mild cases, the most frequent symptoms were fever (n=7) and cough (n=6), followed by fatigue (n=2), myalgia (n=2) and anosmia (n=2). One patient presented only with acute limb ischemia, derived from thrombus in the superficial femoral artery. One patient had radiological features of COVID-19 pneumonia, but did not require hospitalization. The only patient with severe COVID-19 developed pneumonia requiring CPAP, was refractory to tocilizumab (anti-IL6), but recovered after starting ruxolitinib (JAK2-inhibitor). The median time to complete resolution of symptoms was 21 days (7-56).
Conclusions:
The prevalence of infection in our CML pts is similar to that of the overall population, which suggests that they are capable of mounting appropriate antibody response against SARS-CoV-2.
Importantly, in seropositive pts symptoms were mild. Of note is the higher prevalence in the BAME community and underlines the potential role of socioeconomic factors in disease transmission. Expansion of this CML cohort and serial antibody testing in seropositive patients will provide further information regarding prevalence and durability of serological responses.
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Milojkovic:Incyte: Consultancy, Honoraria; Bristol-Myers Squibb: Consultancy, Honoraria; Novartis: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria. Apperley:Bristol Myers Squibb: Honoraria, Speakers Bureau; Incyte: Honoraria, Research Funding, Speakers Bureau; Pfizer: Honoraria, Research Funding, Speakers Bureau; Novartis: Honoraria, Speakers Bureau.
Chronic myeloid leukaemia (CML) is one of the most well characterised human malignancies. Most patients have a cytogenetically visible translocation between chromosomes 9 and 22 which generates the ...pathognomonic BCR::ABL1 fusion gene. The derivative chromosome 22 ('Philadelphia' or Ph chromosome) usually harbours the fusion gene encoding a constitutively active ABL1 kinase domain. A small subset of patients have no visible translocation. Historically, these 'Philadelphia chromosome negative' patients caused diagnostic confusion between CML and other myeloproliferative neoplasms; it is now well established that the BCR::ABL1 fusion gene can be generated via submicroscopic intrachromosomal insertion of ABL1 sequence into BCR, or, more rarely, of BCR into ABL1. The fusion genes arising from cryptic insertions are not detectable via G-banded chromosome analysis karyotype but can nevertheless always be detected using fluorescence in situ hybridisation (FISH) and/or qualitative reverse transcriptase PCR.
A 43-year-old female presented with suspected CML in 2007; however, contemporaneous gold standard laboratory investigations, G-banded chromosome analysis and FISH, were both negative. The reverse transcriptase quantitative PCR (RT-qPCR) assay available at the time, which was capable of detecting the common BCR::ABL1 transcripts (e13a2/e14a2), was also negative. Upon review in 2009, the newly recommended reverse transcriptase multiplex PCR (capable of detecting all BCR::ABL1 transcripts including the atypical ones) subsequently detected an e19a2 fusion. The patient then responded to tyrosine kinase inhibitor therapy. In contrast, FISH studies of both samples with three commercially available probes remained consistently negative. Retrospective whole genome sequencing, undertaken as part of the 100,000 Genomes Project, has now revealed that the patient's BCR::ABL1 fusion gene arose via a uniquely small insertion of 122 kb ABL1 sequences into BCR.
We present a patient with suspected chronic myeloid leukaemia whose genetic investigations were originally negative at the time of diagnosis despite the use of contemporaneous gold standard methods. This is the first report of a FISH-negative, BCR::ABL1 positive CML which demonstrates that, even after sixty years of research into one of the most well understood human malignancies, whole genome sequencing can yield novel diagnostic findings in CML.
Summary
The clinical outcome of chronic myeloid leukaemia patients has vastly improved since the introduction of tyrosine kinase inhibitor treatment, with a significant proportion of patients able to ...achieve treatment‐free remission. However, studies have shown that patients with the e13a2 transcript were less likely to achieve major molecular response compared to those with e14a2 transcripts. Most quantitative polymerase chain reaction (PCR) assays for detection of the BCR–ABL1 fusion gene do not differentiate between the two transcripts and we therefore hypothesised that technical bias linked to the qPCR assay could partially explain the discrepancy in outcomes. We designed an e14a2‐specific assay and identified no difference in results compared to an e13a2 standard assay. We then demonstrated that the commercial e14a2 standards were causing a significant overestimation of the e13a2 transcripts. Finally, we reviewed patient management after the qPCR values were corrected, using our new evaluation. We concluded that despite statistically significant differences in qPCR results, there was no impact on patient management or outcome. We conclude that, at least in our institution, it would be inappropriate to perform separate assays for patients with e13a2 or e14a2.
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