0	6	Signal	Signal	NNP
7	19	transduction	transduction	NN
20	33	abnormalities	abnormality	NNS
34	36	in	in	IN
37	38	T	t	NN
39	50	lymphocytes	lymphocyte	NNS
51	55	from	from	IN
56	64	patients	patient	NNS
65	69	with	with	IN
70	78	advanced	advance	VBN
79	84	renal	renal	JJ
85	94	carcinoma	carcinoma	NN
94	95	:	:	:
96	104	clinical	clinical	JJ
105	114	relevance	relevance	NN
115	118	and	and	CC
119	126	effects	effect	NNS
127	129	of	of	IN
130	138	cytokine	cytokine	NN
139	146	therapy	therapy	NN
146	147	.	.	.

149	156	Studies	Study	NNPS
157	161	have	have	VBP
162	174	demonstrated	demonstrate	VBN
175	188	abnormalities	abnormality	NNS
189	191	of	of	IN
192	195	the	the	DT
196	206	CD3/T-cell	cd3/t-cell	NN
207	214	antigen	antigen	NN
215	223	receptor	receptor	NN
224	225	(	(	(
225	228	TCR	TCR	NNP
228	229	)	)	)
230	233	and	and	CC
234	242	pathways	pathway	NNS
243	245	of	of	IN
246	252	signal	signal	NN
253	265	transduction	transduction	NN
266	268	in	in	IN
269	270	T	t	NN
271	282	lymphocytes	lymphocyte	NNS
283	287	from	from	IN
288	295	animals	animal	NNS
296	299	and	and	CC
300	308	patients	patient	NNS
309	313	with	with	IN
314	322	advanced	advanced	JJ
323	333	malignancy	malignancy	NN
333	334	.	.	.

335	345	Diminished	diminish	VBN
346	356	expression	expression	NN
357	359	of	of	IN
360	367	TCRzeta	TCRzeta	NNP
368	371	and	and	CC
372	380	p56(lck)	p56(lck)	NNP
381	385	that	that	WDT
386	389	are	be	VBP
390	400	associated	associate	VBN
401	405	with	with	IN
406	409	the	the	DT
410	413	TCR	TCR	NNP
414	417	and	and	CC
418	425	reduced	reduce	VBN
426	433	nuclear	nuclear	JJ
434	446	localization	localization	NN
447	449	of	of	IN
450	454	RelA	RelA	NNP
455	465	containing	contain	VBG
466	473	nuclear	nuclear	JJ
474	480	factor	factor	NN
481	487	kappaB	kappaB	NNP
488	489	(	(	(
489	497	NFkappaB	NFkappaB	NNP
497	498	)	)	)
499	508	complexes	complex	NNS
509	513	have	have	VBP
514	518	been	be	VBN
519	524	noted	note	VBN
524	525	.	.	.

526	531	These	these	DT
532	539	defects	defect	NNS
540	544	have	have	VBP
545	549	been	be	VBN
550	559	described	describe	VBN
560	562	in	in	IN
563	564	T	t	NN
565	570	cells	cell	NNS
571	575	from	from	IN
576	584	patients	patient	NNS
585	589	with	with	IN
590	599	malignant	malignant	JJ
600	608	melanoma	melanoma	NN
608	609	,	,	,
610	615	renal	renal	JJ
616	620	cell	cell	NN
621	630	carcinoma	carcinoma	NN
631	632	(	(	(
632	635	RCC	RCC	NNP
635	636	)	)	)
636	637	,	,	,
638	645	ovarian	ovarian	JJ
646	652	cancer	cancer	NN
652	653	,	,	,
654	657	and	and	CC
658	668	colorectal	colorectal	JJ
669	675	cancer	cancer	NN
675	676	.	.	.

677	688	Preliminary	preliminary	JJ
689	701	observations	observation	NNS
702	706	also	also	RB
707	715	indicate	indicate	VBP
716	724	possible	possible	JJ
725	736	correlation	correlation	NN
737	741	with	with	IN
742	750	clinical	clinical	JJ
751	760	variables	variable	NNS
761	765	such	such	JJ
766	768	as	as	IN
769	774	stage	stage	NN
775	777	in	in	IN
778	786	selected	select	VBN
787	796	instances	instance	NNS
796	797	.	.	.

798	800	To	to	TO
801	808	further	further	RB
809	821	characterize	characterize	VB
822	829	altered	altered	JJ
830	840	expression	expression	NN
841	843	of	of	IN
844	851	TCRzeta	TCRzeta	NNP
851	852	,	,	,
853	861	p56(lck)	p56(lck)	NN
861	862	,	,	,
863	866	and	and	CC
867	875	impaired	impaired	JJ
876	886	activation	activation	NN
887	889	of	of	IN
890	898	NFkappaB	NFkappaB	NNP
898	899	,	,	,
900	901	T	t	NN
902	913	lymphocytes	lymphocyte	NNS
914	918	were	be	VBD
919	927	obtained	obtain	VBN
928	932	from	from	IN
933	935	65	65	CD
936	944	patients	patient	NNS
945	949	with	with	IN
950	953	RCC	RCC	NNP
953	954	,	,	,
955	958	the	the	DT
959	967	majority	majority	NN
968	970	of	of	IN
971	975	whom	whom	WP
976	980	were	be	VBD
981	990	receiving	receive	VBG
991	1002	combination	combination	NN
1003	1011	cytokine	cytokine	NN
1012	1019	therapy	therapy	NN
1020	1021	[	[	(
1021	1032	interleukin	interleukin	NN
1033	1034	(	(	(
1034	1039	IL)-2	IL)-2	NNP
1039	1040	,	,	,
1041	1044	IFN	ifn	NN
1045	1061	alpha-containing	alpha-containing	JJ
1062	1070	regimens	regimen	NNS
1070	1071	]	]	)
1072	1075	and	and	CC
1076	1078	37	37	CD
1079	1086	control	control	JJ
1087	1098	individuals	individual	NNS
1098	1099	.	.	.

1100	1102	In	in	IN
1103	1105	29	29	CD
1106	1108	of	of	IN
1109	1114	these	these	DT
1115	1123	patients	patient	NNS
1123	1124	,	,	,
1125	1131	levels	level	NNS
1132	1134	of	of	IN
1135	1142	TCRzeta	TCRzeta	NNP
1143	1146	and	and	CC
1147	1155	p56(lck)	p56(lck)	NNP
1156	1160	were	be	VBD
1161	1171	determined	determine	VBN
1172	1174	by	by	IN
1175	1182	Western	western	JJ
1183	1188	blots	blot	NNS
1189	1191	of	of	IN
1192	1198	T-cell	t-cell	NN
1199	1206	lysates	lysate	NNS
1207	1210	and	and	CC
1211	1226	semiquantitated	semiquantitate	VBN
1227	1232	using	use	VBG
1233	1245	densitometry	densitometry	NN
1245	1246	.	.	.

1247	1255	Relative	relative	JJ
1256	1262	levels	level	NNS
1263	1267	were	be	VBD
1268	1272	then	then	RB
1273	1283	correlated	correlate	VBN
1284	1288	with	with	IN
1289	1290	a	a	DT
1291	1297	series	series	NN
1298	1300	of	of	IN
1301	1309	clinical	clinical	JJ
1310	1319	variables	variable	NNS
1320	1329	including	include	VBG
1330	1338	response	response	NN
1339	1341	to	to	TO
1342	1349	therapy	therapy	NN
1349	1350	,	,	,
1351	1362	performance	performance	NN
1363	1369	status	status	NN
1369	1370	,	,	,
1371	1379	survival	survival	NN
1379	1380	,	,	,
1381	1388	disease	disease	NN
1389	1394	sites	site	NNS
1394	1395	,	,	,
1396	1399	age	age	NN
1399	1400	,	,	,
1401	1404	and	and	CC
1405	1411	others	other	NNS
1411	1412	.	.	.

1413	1415	In	in	IN
1416	1423	another	another	DT
1424	1429	group	group	NN
1430	1432	of	of	IN
1433	1435	28	28	CD
1436	1444	patients	patient	NNS
1445	1446	(	(	(
1446	1451	three	three	CD
1452	1463	individuals	individual	NNS
1464	1468	from	from	IN
1469	1472	the	the	DT
1473	1478	first	first	JJ
1479	1484	group	group	NN
1484	1485	)	)	)
1485	1486	,	,	,
1487	1490	the	the	DT
1491	1500	frequency	frequency	NN
1501	1503	of	of	IN
1504	1512	abnormal	abnormal	JJ
1513	1521	NFkappaB	NFkappaB	NNP
1522	1532	activation	activation	NN
1533	1536	was	be	VBD
1537	1544	studied	study	VBN
1545	1550	using	use	VBG
1551	1566	electrophoretic	electrophoretic	JJ
1567	1575	mobility	mobility	NN
1576	1581	shift	shift	NN
1582	1588	assays	assay	NNS
1589	1594	after	after	IN
1595	1605	activation	activation	NN
1606	1608	of	of	IN
1609	1610	T	t	NN
1611	1616	cells	cell	NNS
1617	1621	with	with	IN
1622	1629	phorbol	phorbol	NN
1630	1639	myristate	myristate	NN
1640	1657	acetate/ionomycin	acetate/ionomycin	NN
1658	1660	or	or	CC
1661	1669	anti-CD3	anti-cd3	JJ
1670	1680	monoclonal	monoclonal	JJ
1681	1689	antibody	antibody	NN
1689	1690	.	.	.

1691	1698	Changes	change	NNS
1699	1701	in	in	IN
1702	1707	these	these	DT
1708	1717	signaling	signal	VBG
1718	1727	molecules	molecule	NNS
1728	1734	during	during	IN
1735	1743	cytokine	cytokine	NN
1744	1753	treatment	treatment	NN
1754	1758	were	be	VBD
1759	1763	also	also	RB
1764	1776	investigated	investigate	VBN
1776	1777	.	.	.

1778	1785	TCRzeta	TCRzeta	NNP
1786	1789	and	and	CC
1790	1798	p56(lck)	p56(lck)	NNP
1799	1803	were	be	VBD
1804	1812	detected	detect	VBN
1813	1815	in	in	IN
1816	1819	the	the	DT
1820	1830	peripheral	peripheral	JJ
1831	1836	blood	blood	NN
1837	1838	T	t	NN
1839	1844	cells	cell	NNS
1845	1847	in	in	IN
1848	1850	27	27	CD
1851	1853	of	of	IN
1854	1856	29	29	CD
1857	1865	patients	patient	NNS
1865	1866	,	,	,
1867	1870	and	and	CC
1871	1878	overall	overall	RB
1878	1879	,	,	,
1880	1887	reduced	reduce	VBN
1888	1894	levels	level	NNS
1895	1899	were	be	VBD
1900	1905	noted	note	VBN
1906	1914	visually	visually	RB
1915	1917	in	in	IN
1918	1920	12	12	CD
1921	1923	of	of	IN
1924	1926	29	29	CD
1927	1928	(	(	(
1928	1930	41	41	CD
1930	1931	%	%	NN
1931	1932	)	)	)
1933	1936	and	and	CC
1937	1939	13	13	CD
1940	1942	of	of	IN
1943	1945	29	29	CD
1946	1947	(	(	(
1947	1949	45	45	CD
1949	1950	%	%	NN
1950	1951	)	)	)
1952	1963	individuals	individual	NNS
1963	1964	,	,	,
1965	1977	respectively	respectively	RB
1977	1978	.	.	.

1979	1983	When	when	WRB
1984	1990	levels	level	NNS
1991	1995	were	be	VBD
1996	2011	semiquantitated	semiquantitate	VBN
2012	2017	using	use	VBG
2018	2030	densitometry	densitometry	NN
2030	2031	,	,	,
2032	2043	significant	significant	JJ
2044	2053	decreases	decrease	NNS
2054	2056	of	of	IN
2057	2064	TCRzeta	TCRzeta	NNP
2065	2066	(	(	(
2066	2067	P	p	NN
2068	2069	=	=	SYM
2070	2075	0.029	0.029	CD
2075	2076	)	)	)
2077	2080	and	and	CC
2081	2089	p56(lck)	p56(lck)	NNP
2090	2091	(	(	(
2091	2092	P	p	NN
2093	2094	=	=	SYM
2095	2100	0.029	0.029	CD
2100	2101	)	)	)
2102	2105	but	but	CC
2106	2109	not	not	RB
2110	2120	CD3epsilon	CD3epsilon	NNP
2121	2122	(	(	(
2122	2123	P	p	NN
2124	2125	=	=	SYM
2126	2131	0.131	0.131	CD
2131	2132	)	)	)
2132	2133	,	,	,
2134	2142	compared	compare	VBN
2143	2147	with	with	IN
2148	2155	control	control	NN
2156	2162	levels	level	NNS
2162	2163	,	,	,
2164	2168	were	be	VBD
2169	2174	found	find	VBN
2174	2175	.	.	.

2176	2178	In	in	IN
2179	2187	patients	patient	NNS
2188	2195	treated	treat	VBN
2196	2200	with	with	IN
2201	2209	IL-2/IFN	il-2/ifn	NN
2210	2221	alpha-based	alpha-based	JJ
2222	2229	therapy	therapy	NN
2229	2230	,	,	,
2231	2239	relative	relative	JJ
2240	2246	levels	level	NNS
2247	2249	of	of	IN
2250	2257	TCRzeta	TCRzeta	NNP
2258	2267	increased	increase	VBD
2268	2281	significantly	significantly	RB
2282	2283	(	(	(
2283	2284	P	p	NN
2285	2286	=	=	SYM
2287	2292	0.002	0.002	CD
2292	2293	)	)	)
2294	2296	on	on	IN
2297	2300	day	day	NN
2301	2303	15	15	CD
2304	2306	of	of	IN
2307	2312	cycle	cycle	NN
2313	2316	one	one	CD
2317	2325	compared	compare	VBN
2326	2330	with	with	IN
2331	2334	the	the	DT
2335	2343	baseline	baseline	NN
2343	2344	.	.	.

2345	2357	Correlations	correlation	NNS
2358	2360	of	of	IN
2361	2368	TCRzeta	TCRzeta	NNP
2369	2371	or	or	CC
2372	2380	p56(lck)	p56(lck)	NN
2381	2387	levels	level	NNS
2388	2392	with	with	IN
2393	2401	response	response	NN
2402	2404	or	or	CC
2405	2412	disease	disease	NN
2413	2422	variables	variable	NNS
2422	2423	,	,	,
2424	2430	except	except	IN
2431	2434	for	for	IN
2435	2440	lower	low	JJR
2441	2448	TCRzeta	TCRzeta	NNP
2449	2455	levels	level	NNS
2456	2457	(	(	(
2457	2458	P	p	NN
2459	2460	<	<	SYM
2461	2466	0.001	0.001	CD
2466	2467	)	)	)
2468	2470	in	in	IN
2471	2474	the	the	DT
2475	2483	presence	presence	NN
2484	2486	of	of	IN
2487	2491	bone	bone	NN
2492	2502	metastases	metastasis	NNS
2502	2503	,	,	,
2504	2508	were	be	VBD
2509	2512	not	not	RB
2513	2518	found	find	VBN
2518	2519	.	.	.

2520	2528	Abnormal	abnormal	JJ
2529	2537	NFkappaB	NFkappaB	NNP
2538	2548	activation	activation	NN
2549	2554	after	after	IN
2555	2566	stimulation	stimulation	NN
2567	2571	with	with	IN
2572	2579	phorbol	phorbol	NN
2580	2589	myristate	myristate	NN
2590	2607	acetate/ionomycin	acetate/ionomycin	NN
2608	2614	and/or	and/or	CC
2615	2623	anti-CD3	anti-cd3	JJ
2624	2634	monoclonal	monoclonal	JJ
2635	2643	antibody	antibody	NN
2644	2647	was	be	VBD
2648	2653	found	find	VBN
2654	2656	in	in	IN
2657	2659	59	59	CD
2659	2660	%	%	NN
2661	2663	of	of	IN
2664	2672	patients	patient	NNS
2673	2674	(	(	(
2674	2676	17	17	CD
2677	2679	of	of	IN
2680	2682	28	28	CD
2682	2683	)	)	)
2684	2687	and	and	CC
2688	2691	was	be	VBD
2692	2695	not	not	RB
2696	2705	accounted	account	VBN
2706	2709	for	for	IN
2710	2712	by	by	IN
2713	2716	the	the	DT
2717	2725	advanced	advanced	JJ
2726	2729	age	age	NN
2730	2732	of	of	IN
2733	2736	the	the	DT
2737	2742	study	study	NN
2743	2749	cohort	cohort	NN
2749	2750	.	.	.

2751	2761	Activation	Activation	NNP
2762	2764	of	of	IN
2765	2773	NFkappaB	NFkappaB	NNP
2774	2776	in	in	IN
2777	2787	peripheral	peripheral	JJ
2788	2793	blood	blood	NN
2794	2795	T	t	NN
2796	2801	cells	cell	NNS
2802	2805	was	be	VBD
2806	2815	inducible	inducible	JJ
2816	2822	during	during	IN
2823	2831	cytokine	cytokine	NN
2832	2839	therapy	therapy	NN
2840	2842	in	in	IN
2843	2847	four	four	CD
2848	2850	of	of	IN
2851	2854	six	six	CD
2855	2866	individuals	individual	NNS
2867	2870	who	who	WP
2871	2880	displayed	display	VBD
2881	2889	impaired	impaired	JJ
2890	2898	NFkappaB	NFkappaB	NNP
2899	2907	activity	activity	NN
2908	2913	prior	prior	RB
2914	2916	to	to	TO
2917	2924	therapy	therapy	NN
2924	2925	.	.	.

2926	2934	Moreover	moreover	RB
2934	2935	,	,	,
2936	2944	impaired	impaired	JJ
2945	2955	activation	activation	NN
2956	2958	of	of	IN
2959	2967	NFkappaB	NFkappaB	NNP
2968	2972	does	do	VBZ
2973	2976	not	not	RB
2977	2983	appear	appear	VB
2984	2990	linked	link	VBN
2991	2993	to	to	TO
2994	2995	a	a	DT
2996	3005	reduction	reduction	NN
3006	3008	of	of	IN
3009	3016	TCRzeta	TCRzeta	NNP
3017	3027	expression	expression	NN
3027	3028	,	,	,
3029	3036	because	because	IN
3037	3039	in	in	IN
3040	3044	five	five	CD
3045	3053	patients	patient	NNS
3053	3054	,	,	,
3055	3061	normal	normal	JJ
3062	3069	TCRzeta	TCRzeta	NNP
3070	3076	levels	level	NNS
3077	3081	were	be	VBD
3082	3089	present	present	JJ
3090	3098	although	although	IN
3099	3105	kappaB	kappab	NN
3106	3113	binding	binding	NN
3114	3117	was	be	VBD
3118	3121	not	not	RB
3122	3131	inducible	inducible	JJ
3131	3132	.	.	.

3133	3135	In	in	IN
3136	3139	the	the	DT
3140	3148	majority	majority	NN
3149	3151	of	of	IN
3152	3160	patients	patient	NNS
3161	3165	with	with	IN
3166	3174	advanced	advance	VBN
3175	3178	RCC	RCC	NNP
3178	3179	,	,	,
3180	3190	peripheral	peripheral	JJ
3191	3196	blood	blood	NN
3197	3198	T	t	NN
3199	3204	cells	cell	NNS
3205	3212	express	express	VBP
3213	3220	TCRzeta	TCRzeta	NNP
3221	3224	and	and	CC
3225	3233	p56(lck)	p56(lck)	NNP
3233	3234	,	,	,
3235	3238	and	and	CC
3239	3241	in	in	IN
3242	3243	a	a	DT
3244	3250	subset	subset	NN
3250	3251	,	,	,
3252	3259	reduced	reduce	VBD
3260	3266	levels	level	NNS
3267	3269	of	of	IN
3270	3275	these	these	DT
3276	3283	TCRzeta	TCRzeta	NNP
3284	3294	associated	associated	JJ
3295	3304	molecules	molecule	NNS
3305	3308	are	be	VBP
3309	3313	seen	see	VBN
3314	3318	that	that	WDT
3319	3322	may	may	MD
3323	3331	increase	increase	VB
3332	3338	during	during	IN
3339	3353	cytokine-based	cytokine-based	JJ
3354	3361	therapy	therapy	NN
3361	3362	.	.	.

3363	3371	Abnormal	abnormal	JJ
3372	3382	activation	activation	NN
3383	3385	of	of	IN
3386	3394	NFkappaB	NFkappaB	NNP
3395	3397	is	be	VBZ
3398	3402	also	also	RB
3403	3410	present	present	JJ
3411	3413	in	in	IN
3414	3417	>50	>50	CD
3417	3418	%	%	NN
3419	3421	of	of	IN
3422	3430	patients	patient	NNS
3431	3434	and	and	CC
3435	3438	may	may	MD
3439	3443	also	also	RB
3444	3450	revert	revert	VB
3451	3453	to	to	TO
3454	3460	normal	normal	JJ
3461	3467	during	during	IN
3468	3476	IL-2/IFN	il-2/ifn	NN
3477	3488	alpha-based	alpha-based	JJ
3489	3498	treatment	treatment	NN
3498	3499	.	.	.

3500	3504	This	this	DT
3505	3515	alteration	alteration	NN
3516	3518	in	in	IN
3519	3527	NFkappaB	NFkappaB	NNP
3528	3538	activation	activation	NN
3539	3547	occurred	occur	VBD
3548	3550	in	in	IN
3551	3554	the	the	DT
3555	3563	presence	presence	NN
3564	3566	of	of	IN
3567	3573	normal	normal	JJ
3574	3584	expression	expression	NN
3585	3587	of	of	IN
3588	3606	TCRzeta-associated	tcrzeta-associated	JJ
3607	3616	signaling	signaling	NN
3617	3625	elements	element	NNS
3625	3626	.	.	.

3627	3630	The	the	DT
3631	3639	clinical	clinical	JJ
3640	3652	significance	significance	NN
3653	3655	of	of	IN
3656	3661	these	these	DT
3662	3670	findings	finding	NNS
3671	3678	remains	remain	VBZ
3679	3686	unclear	unclear	JJ
3686	3687	.	.	.