133 research outputs found
The influence of bumetanide on the membrane potential of mouse skeletal muscle cells in isotonic and hypertonic media
Evaluation of early implementation of tumor-infiltrating lymphocytes in treating advanced melanoma in an academic setting:a constructive technology analysis
DHPR activation underlies SR Ca2+ release induced by osmotic stress in isolated rat skeletal muscle fibers
Changes in skeletal muscle volume induce localized sarcoplasmic reticulum (SR) Ca2+ release (LCR) events, which are sustained for many minutes, suggesting a possible signaling role in plasticity or pathology. However, the mechanism by which cell volume influences SR Ca2+ release is uncertain. In the present study, rat flexor digitorum brevis fibers were superfused with isoosmotic Tyrode's solution before exposure to either hyperosmotic (404 mOsm) or hypoosmotic (254 mOsm) solutions, and the effects on cell volume, membrane potential (Em), and intracellular Ca2+ ([Ca2+]i) were determined. To allow comparison with previous studies, solutions were made hyperosmotic by the addition of sugars or divalent cations, or they were made hypoosmotic by reducing [NaCl]o. All hyperosmotic solutions induced a sustained decrease in cell volume, which was accompanied by membrane depolarization (by 14â18 mV; n = 40) and SR Ca2+ release. However, sugar solutions caused a global increase in [Ca2+]i, whereas solutions made hyperosmotic by the addition of divalent cations only induced LCR. Decreasing osmolarity induced an increase in cell volume and a negative shift in Em (by 15.04 Âą 1.85 mV; n = 8), whereas [Ca2+]i was unaffected. However, on return to the isoosmotic solution, restoration of cell volume and Em was associated with LCR. Both global and localized SR Ca2+ release were abolished by the dihydropyridine receptor inhibitor nifedipine by sustained depolarization of the sarcolemmal or by the addition of the ryanodine receptor 1 inhibitor tetracaine. Inhibitors of the Na-K-2Cl (NKCC) cotransporter markedly inhibited the depolarization associated with hyperosmotic shrinkage and the associated SR Ca2+ release. These findings suggest (1) that the depolarization that accompanies a decrease in cell volume is the primary event leading to SR Ca2+ release, and (2) that volume-dependent regulation of the NKCC cotransporter contributes to the observed changes in Em. The differing effects of the osmotic agents can be explained by the screening of fixed charges by divalent ions
Discontinuation of anti-PD-1 antibody therapy in the absence of disease progression or treatment limiting toxicity : clinical outcomes in advanced melanoma
Background Programmed cell death protein 1 (PD-1) blocking monoclonal antibodies improve the overall survival of patients with advanced melanoma but the optimal duration of treatment has not been established. Patients and Methods This academic real-world cohort study investigated the outcome of 185 advanced melanoma patients who electively discontinued anti-PD-1 therapy with pembrolizumab (N=167) or nivolumab (N=18) in the absence of disease progression (PD) or treatment limiting toxicity (TLT) at 14 medical centres across Europe and Australia. Results Median time on treatment was 12months (range 0.7-43). The best objective tumour response at the time of treatment discontinuation was complete response (CR) in 117 (63%) patients, partial response (PR) in 44 (24%) patients and stable disease (SD) in 16 (9%) patients; 8 (4%) patients had no evaluable disease (NE). After a median follow-up of 18months (range 0.7-48) after treatment discontinuation, 78% of patients remained free of progression. Median time to progression was 12months (range 2-23). PD was less frequent in patients with CR (14%) compared with patients with PR (32%) and SD (50%). Six out of 19 (32%) patients who were retreated with an anti-PD-1 at the time of PD obtained a new antitumour response. Conclusions In this real-world cohort of advanced melanoma patients discontinuing anti-PD-1 therapy in the absence of TLT or PD, the duration of anti-PD-1 therapy was shorter when compared with clinical trials. In patients obtaining a CR, and being treated for >6months, the risk of relapse after treatment discontinuation was low. Patients achieving a PR or SD as best tumour response were at higher risk for progression after discontinuing therapy, and defining optimal treatment duration in such patients deserves further study. Retreatment with an anti-PD-1 at the time of progression may lead to renewed antitumour activity in some patients. Clinical trial registration NCT02673970 (https://clinicaltrials.gov/ct2/show/NCT02673970?cond=melanoma&cntry=BE&city=Jette&rank=3)Peer reviewe
Systematic review and case series: flexible sigmoidoscopy identifies most cases of checkpoint inhibitorâinduced colitis
Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/149542/1/apt15263_am.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/149542/2/apt15263.pd
Clinical aspects of immunotherapy and targeted therapy of advanced melanoma
This thesis focused on different aspects of melanoma
treatment with immunotherapy and targeted therapy. In chapter 2 we search for
biomarkers that could be associated with overall survival in patients treated
with ipilimumab. In chapter 3 we describe diarrea, a commonly seen side
effect of immunotherapy. Here we show that there is no significant
correlation between grade of diarrhea and severity of colitis as seen during
endoscopy. Chapters 4 and 5 describe patients with brain metastases and/or
leptomeningeal metastases. In chapter 4 we show the difference in overall
survival in patients treated with vemurafenib, dabrafenib or the combination
of dabrafenib + trametinib. Chapter 5 focusses on the treatment of
leptomeningeal metastases. Here a significant difference in overall survival
was noted between treated and untreated patients. Furthermore LDH was a
predictive biomarker for overall survival. In chapter 6 we show that treating
patients with vemurafenib beyond progression of disease has a significant
impact on overall survival. Lastly in chapter 7 we review the past, present
and future of treating patients with different kinds of cancer with
tumor-infiltrating lymphocytes.
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Clinical aspects of immunotherapy and targeted therapy of advanced melanoma
This thesis focused on different aspects of melanoma
treatment with immunotherapy and targeted therapy. In chapter 2 we search for
biomarkers that could be associated with overall survival in patients treated
with ipilimumab. In chapter 3 we describe diarrea, a commonly seen side
effect of immunotherapy. Here we show that there is no significant
correlation between grade of diarrhea and severity of colitis as seen during
endoscopy. Chapters 4 and 5 describe patients with brain metastases and/or
leptomeningeal metastases. In chapter 4 we show the difference in overall
survival in patients treated with vemurafenib, dabrafenib or the combination
of dabrafenib + trametinib. Chapter 5 focusses on the treatment of
leptomeningeal metastases. Here a significant difference in overall survival
was noted between treated and untreated patients. Furthermore LDH was a
predictive biomarker for overall survival. In chapter 6 we show that treating
patients with vemurafenib beyond progression of disease has a significant
impact on overall survival. Lastly in chapter 7 we review the past, present
and future of treating patients with different kinds of cancer with
tumor-infiltrating lymphocytes.
LUMC / Geneeskund
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