Lewis, Amber Loren O. Carlson, Sheila R. Umlauf, Yulia V. Surovtseva, Francine M. Blood Adv ; 4 10 : — Cutaneous T-cell lymphoma CTCL is a malignancy of skin-homing T lymphocytes that is more likely to involve the peripheral blood in advanced stages. For such patients with advanced disease, there are few available systemic treatment options, and prognosis remains poor. JAK inhibition decreased expression of BCL2 in the high-responder samples, suggesting a putative mechanism for this combination activity.
Such preclinical assessments help inform prioritization for combination targeted drug approaches for clinical utilization in the treatment of CTCL. These data have informed the screening of recently discovered agents targeting these common pathways.
In normal T cells, stimulation occurs with antigen presentation; however, in CTCL cells, mutations give rise to heightened activation of this cascade, driving T-cell proliferation and aberrant cytokine production. One such agent, ruxolitinib a JAK inhibitor , has been approved for myeloproliferative disorders and is being investigated for use in lymphomas. Through in vitro preclinical assessment against CTCL patient—derived cells, we herein show the fuller potential of these agents, alone and in combination, as potential treatment modalities for CTCL.
Taken together, our data strongly suggest a potential role for JAK inhibition in the treatment of CTCL and lay the groundwork whereby a strategic combination formulation may move forward for clinical assessment. Written informed consent was obtained from all subjects in accordance with the Yale Human Investigational Review Board.
Peripheral blood samples from consenting patients and healthy donors were collected in lithium heparin tubes, and peripheral blood mononuclear cells were separated from whole blood as previously reported. Purified blood mononuclear cells from patient samples were analyzed by fluorescence in situ hybridization as previously described.
Twenty nanoliters of compound was then transferred into assay plates using Echo acoustic liquid handler Labcyte. The same compound source plate was used for both single-drug and combination drug additions. Final DMSO concentration in the assay was 0. Eighteen to 24 replicates of negative control 0.
Following 72 hours incubation with the compounds, CellTiter-Glo reagent Promega, Madison, WI was added to measure total adenosine triphosphate accumulation as a readout for cell viability. RNA was extracted and converted to complementary DNA, and TaqMan assays Thermo Fisher Scientific were used to examine gene expression differences relative to normal controls as previously reported. Seven patients CTCL subtypes are subtypes at the time of diagnosis. Current therapy is defined as treatment at the time of experiment.
B stage based on International Society for Cutaneous Lymphomas classification and the criteria proposed by Gibson et al. ID, identifier; ND, not distinguished. A Comparison of IC 50 values. CTCL patient samples, control samples, and CTCL cell lines revealed statistically significant differences in response to mivebresib and bortezomib.
The median and mean IC 50 for patient samples were 2. Bii IC 50 differences for B1 and B2 stage to ruxolitinib were found to be nonsignificant. C Dose—response curves for patient samples C and CTCL cell lines D for ruxolitinib i , mivebresib ii , venetoclax iii , vorinostat iv , and bortezomib v. Sensitivities to mivebresib, venetoclax, and vorinostat reflected results previously published by our group.
At the wide range of concentrations tested, CTCL patient samples and normal control samples showed consistent resistance to cytotoxicity by bexarotene, talazoparib, and methotrexate: they exhibited no decrease in cell viability at any concentration tested in vitro. In contrast, the 5 CTCL cell lines showed variable sensitivity to these 3 agents supplemental Figure 1.
The IC 50 for ruxolitinib ranged widely from 1. Less than one-half of the CTCL patient samples 7 of 19 [ IC 50 values of low-responders were comparable to, and even greater than, those of normal control lymphocytes mean, There was no statistically significant difference in response to ruxolitinib between patients classified as B1 and B2 Figure 1Bii. Our results highlight the potential of JAK inhibition by ruxolitinib against patient-derived malignant CTCL cells as a potentially promising agent on preclinical assessment.
We also show the lack of consistency of sensitivities of CTCL cell lines to the targeting agents tested, relative to both patient-derived and normal control lymphocytes. These results strongly suggest that preclinical analyses of drug responsivity are of limited value when only CTCL lines are examined.
Results are expressed as a fold change from the mean of normal control samples. B JAK2 expression fold change in malignant patient-derived cells compared with normal lymphocytes may predict response to ruxolitinib in vitro, with higher JAK2 expression moderately correlated to sensitivity.
Fold-potentiation was calculated as fold improvement in percent kill by the combination drug pair relative to a single agent. Results were plotted as a heatmap of combination indices and fold-potentiation for each patient sample supplemental Figure 3. Of note, ruxolitinib in combination with either venetoclax, vorinostat, or bortezomib showed increased cytotoxicity relative to single drug exposure, regardless of single agent sensitivity.
Although principally acting as cytostatic agents, bexarotene, methotrexate, and talazoparib exhibited weak to little cytotoxic effects on CTCL cell viability as single agents; nonetheless, these drugs displayed the capacity to potentiate cytotoxicity induced by venetoclax, vorinostat, bortezomib, and mivebresib when used in combination.
Combination indices for the highest percent kill achieved with each combination are presented in Figure 3Bi. For comparison, fold-potentiation for these same combinations was also plotted Figure 3Bii. Preclinical assessment of targeted drug combinations against CTCL patient—derived samples. CTCL patient cells were incubated with each of 5 targeted agents ruxolitinib, venetoclax, vorinostat, mivebresib, and bortezomib individually to calculate single-agent IC 50 values.
Cells were then incubated with combinations of each drug at 3 concentrations, and the combination index CI was calculated by using the Chou-Talalay method. Resulting CIs were plotted as heatmaps. A Representative heat map of a high-responder to ruxolitinib i and a low-responder to ruxolitinib ii. Strongest synergy was seen with venetoclax plus ruxolitinib and venetoclax plus mivebresib across patient samples. Bii The fold improvement in cytotoxicity for the same concentrations was calculated and plotted for these CTCL patient—derived samples exposed to combinations of ruxolitinib, venetoclax, vorinostat, and mivebresib.
The highest fold potentiation was seen with the combination of ruxolitinib and venetoclax. Adapted from Chou. Because JAK inhibition alone resulted in differential responses among patient-derived malignant CTCL cells, we sought to investigate the degree to which combination approaches might overcome this varied responsiveness.
Patient-derived CTCL samples that were high-responders to ruxolitinib consistently displayed moderate to very strong synergy at the majority of combination concentrations tested. Of note, those patient samples considered low-responders to ruxolitinib also exhibited consistent potentiation of cytotoxicity by agent pairs that included ruxolitinib, particularly when ruxolitinib was used in combination with venetoclax or bortezomib.
Synergy and potentiation assessment of targeted agent combinations using ruxolitinib. A CIs were plotted as heatmaps for patient-derived samples i ; percent kill plotted for the same concentrations ii. Very strong synergy was seen with ruxolitinib and venetoclax across all 5 high-responder patients.
Strong to very strong potentiation was seen among low-responders. B Representative curves of combinations of ruxolitinib with venetoclax i , vorinostat ii , bortezomib iii , and mivebresib iv for a high-responder. The most substantial synergy was observed with ruxolitinib and venetoclax. Representative dose—response curves of the CTCL patient sample that was most sensitive to ruxolitinib are shown in Figure 4B.
Exposure to ruxolitinib or venetoclax alone independently induced total and extrinsic caspase-dependent apoptosis, with a trend toward higher apoptosis observed with venetoclax compared with ruxolitinib. B Caspase-8 activity at 4 hours i , 12 hours ii , and 24 hours iii shown for patient 9 after incubation with ruxolitinib and venetoclax.
Four of the CTCL patient—derived samples were high-responders to ruxolitinib, and 5 were low-responders. Nonetheless, combination exposure to ruxolitinib and venetoclax did not affect gene expression differently than treatment with ruxolitinib alone. This scenario suggests that this combination therapy might benefit patients with advanced CTCL, including those refractory to single-agent therapy. Results expressed as fold change from untreated vehicle controls in high-responders A and low-responders B.
Our data indicate that expression of JAK2 is moderately inversely correlated with sensitivity to ruxolitinib, with higher expression levels portending increased sensitivity. Although such biomarker-response associations have provided justification for personalized medicine approaches to targeted cancer therapy, data have also suggested that combination targeted drug therapy may provide consistent efficacy across a wider variety of patients. Furthermore, the agents eg, methotrexate, talazoparib, bexarotene that showed minimal cytotoxicity when tested alone nonetheless exhibited potentiation of kill by BCL2, HDAC, BET, and proteasome inhibitors when used in combination.
These data suggest a role for both FAS and TNF-related apoptosis-inducing ligand—mediated extrinsic apoptosis, as well as intrinsic apoptosis associated with reductions in antiapoptotic factors in combination therapy with ruxolitinib plus venetoclax.
Decreased BCL2 expression on exposure of ruxolitinib, combined with direct inhibition of BCL2 protein function by venetoclax, suggests a putative mechanism of cooperative activity of these 2 therapies by decreasing both the levels of BCL2 expression as well as BCL2 activity, resulting in increased apoptosis. This scenario was seen in both single-agent and combination studies.
These data highlight the limitations of CTCL cell lines in recapitulating the behavior of patient-derived CTCL cells in vitro, as well as their limited applicability as preclinical models. CTCL is a heterogeneous disease, with patient CTCL cells having a wide diversity of genomic and cellular alterations driving their behavior. In contrast, the majority of cell lines have certain driver mutations that may not reflect the true diversity of disease in patients. Furthermore, prolonged cell culture is likely to result in occurrence of genomic and transcriptomic changes that are beneficial to survival in culture.
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Info Accept Decline. Rate this prediction Facebook Twitter. The most widely played sport in the world has an enormous following in India as well. So much so that ISL betting is a major money-maker in India, where every game sees hundreds of thousands of wagers flowing in.
The home-grown ISL aside, even the international footballing leagues enjoy a massive viewership in India. Not only do international heavyweights like Nadal and Federer enjoy a formidable following in the country, but India has also produced a slew of home-grown superstars. Trivia : Paes and Bhupathi, considered two of the greatest doubles players ever, have had a massive impact on tennis and shaped its popularity in the country. In , the duo won three doubles titles, including the Wimbledon and Rolland Garros.
That year, they reached the finals of the two other Grand Slams as well, a feat that was a first in the Open Era. Thanks to this, tennis betting has been on the rise as well. An increasing number of punters are finding value by wagering on the four Majors, including the Australian Open. Betting on horse racing has always been entrenched in Indian culture.
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Also, ensure the betting site offers live streaming of the races, considering you will want to watch them live , in case you cannot go to the racecourse. Best betting sites in India for horse racing : Sportsbet. If one were to rank, kabaddi would surely follow cricket and football in popularity. The country also hosts the Vivo Pro Kabaddi League, a professional-level competition that attracts some of the biggest names in kabaddi.
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You can choose the same mode you used to deposit the funds to begin with. Yes, they do. In India, you are deemed to attain majority at 18 years unless any particular law specifies otherwise. It is only after you are 18 years old that you can legally take part in sports betting in India. All pre-match betting markets become inactive as soon as a match begins at the toss, in case of cricket betting.
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