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PMC:7696151 / 66063-92818 JSONTXT

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LitCovid-PubTator

Id Subject Object Predicate Lexical cue tao:has_database_id
1925 5-23 Chemical denotes Hydroxychloroquine MESH:D006886
1927 58-61 Chemical denotes HCQ MESH:D006886
1929 281-300 Disease denotes Autoimmune Diseases MESH:D001327
1966 1948-1977 Gene denotes E selectin and thrombomodulin Gene:6401
1967 943-951 Species denotes patients Tax:9606
1968 1116-1124 Species denotes patients Tax:9606
1969 1563-1571 Species denotes patients Tax:9606
1970 2088-2096 Species denotes patients Tax:9606
1971 2623-2631 Species denotes patients Tax:9606
1972 2874-2882 Species denotes patients Tax:9606
1973 3249-3257 Species denotes patients Tax:9606
1974 3507-3515 Species denotes patients Tax:9606
1975 301-304 Chemical denotes HCQ MESH:D006886
1976 615-625 Chemical denotes coadjutant
1977 780-783 Chemical denotes HCQ MESH:D006886
1978 785-799 Chemical denotes sulphasalazine MESH:D012460
1979 1656-1670 Chemical denotes sulphasalazine MESH:D012460
1980 1710-1713 Chemical denotes HCQ MESH:D006886
1981 2168-2171 Chemical denotes MXT MESH:D008727
1982 2184-2198 Chemical denotes sulphasalazine MESH:D012460
1983 2215-2218 Chemical denotes HCQ MESH:D006886
1984 2279-2297 Chemical denotes methylprednisolone MESH:D008775
1985 2310-2323 Chemical denotes triamcinolone MESH:D014221
1986 2681-2684 Chemical denotes HCQ MESH:D006886
1987 2737-2740 Chemical denotes HCQ MESH:D006886
1988 2990-2997 Chemical denotes 18F-FDG MESH:D019788
1989 3079-3093 Chemical denotes sulphasalazine MESH:D012460
1990 3110-3113 Chemical denotes HCQ MESH:D006886
1991 3200-3207 Chemical denotes 18F-FDG MESH:D019788
1992 3291-3294 Chemical denotes HCQ MESH:D006886
1993 3584-3594 Chemical denotes infliximab MESH:D000069285
1994 491-511 Disease denotes rheumatoid arthritis MESH:D001172
1995 637-657 Disease denotes rheumatoid arthritis MESH:D001172
1996 892-912 Disease denotes rheumatoid arthritis MESH:D001172
1997 1594-1614 Disease denotes rheumatoid arthritis MESH:D001172
1998 1849-1867 Disease denotes endothelial injury MESH:D014947
1999 1905-1923 Disease denotes endothelial injury MESH:D014947
2000 2895-2915 Disease denotes rheumatoid arthritis MESH:D001172
2001 3521-3550 Disease denotes juvenile idiopathic arthritis MESH:D001171
2028 4211-4216 Gene denotes IFN-α Gene:111654
2029 3798-3806 Species denotes patients Tax:9606
2030 3958-3964 Species denotes murine Tax:10090
2031 4663-4671 Species denotes patients Tax:9606
2032 4753-4761 Species denotes patients Tax:9606
2033 4831-4839 Species denotes patients Tax:9606
2034 4952-4960 Species denotes patients Tax:9606
2035 3808-3811 Chemical denotes HCQ MESH:D006886
2036 3908-3911 Chemical denotes HCQ MESH:D006886
2037 3992-3995 Chemical denotes HCQ MESH:D006886
2038 4606-4613 Chemical denotes aspirin MESH:D001241
2039 4615-4618 Chemical denotes HCQ MESH:D006886
2040 4858-4865 Chemical denotes aspirin MESH:D001241
2041 4873-4876 Chemical denotes HCQ MESH:D006886
2042 3777-3797 Disease denotes rheumatoid arthritis MESH:D001172
2043 3828-3847 Disease denotes lupus erythematosus MESH:D008180
2044 3857-3875 Disease denotes autoimmune disease MESH:D001327
2045 3887-3906 Disease denotes lupus erythematosus MESH:D008180
2046 3974-3979 Disease denotes lupus MESH:D008180
2047 4248-4253 Disease denotes lupus MESH:D008180
2048 4405-4410 Disease denotes lupus MESH:D008180
2049 4677-4682 Disease denotes lupus MESH:D008180
2050 4702-4712 Disease denotes thrombotic MESH:D013927
2051 4780-4808 Disease denotes cardiovascular complications MESH:D002318
2052 4923-4930 Disease denotes thrombo MESH:D054556
2053 4966-4971 Disease denotes lupus MESH:D008180
2058 5225-5229 Species denotes mice Tax:10090
2059 5022-5025 Chemical denotes HCQ MESH:D006886
2060 5113-5127 Chemical denotes cyclosporine A MESH:D016572
2061 5066-5091 Disease denotes graft-versus-host disease MESH:D006086
2087 5996-6003 Gene denotes insulin Gene:3630
2088 5535-5543 Species denotes patients Tax:9606
2089 5826-5830 Species denotes mice Tax:10090
2090 6238-6241 Species denotes rat Tax:10116
2091 5276-5279 Chemical denotes HCQ MESH:D006886
2092 5460-5463 Chemical denotes HCQ MESH:D006886
2093 5599-5602 Chemical denotes HCQ MESH:D006886
2094 5762-5765 Chemical denotes HCQ MESH:D006886
2095 5900-5909 Chemical denotes tadalafil MESH:D000068581
2096 6056-6059 Chemical denotes HCQ MESH:D006886
2097 6262-6265 Chemical denotes HCQ MESH:D006886
2098 6363-6370 Chemical denotes aspirin MESH:D001241
2099 6374-6385 Chemical denotes clopidogrel MESH:D000077144
2100 6417-6420 Chemical denotes HCQ MESH:D006886
2101 6424-6431 Chemical denotes aspirin MESH:D001241
2102 6598-6614 Chemical denotes arachidonic acid MESH:D016718
2103 5365-5384 Disease denotes glucose homeostasis MESH:D044882
2104 5484-5512 Disease denotes cardiovascular complications MESH:D002318
2105 5666-5689 Disease denotes cardiovascular diseases MESH:D002318
2106 5779-5806 Disease denotes ischemia-reperfusion injury MESH:D015427
2107 5817-5825 Disease denotes diabetic MESH:D003920
2108 5946-5964 Disease denotes myocardial infarct MESH:D009203
2109 6151-6174 Disease denotes ischemic cardiomyopathy MESH:D003324
2110 6180-6194 Disease denotes cardiac stroke MESH:D020521
2111 6287-6307 Disease denotes platelet aggregation MESH:D001791
2157 7440-7444 Gene denotes P-gp Gene:283871
2158 7446-7451 Gene denotes ABCB1 Gene:5243
2159 8236-8240 Gene denotes KRAS Gene:16653
2160 8266-8269 Gene denotes p53 Gene:22060
2161 8413-8416 Gene denotes p53 Gene:22060
2162 8580-8583 Gene denotes p53 Gene:22060
2163 8609-8612 Gene denotes p53 Gene:22060
2164 9033-9036 Gene denotes p53 Gene:22060
2165 9198-9201 Gene denotes p53 Gene:22060
2166 9270-9274 Gene denotes KRAS Gene:16653
2167 8064-8070 Species denotes murine Tax:10090
2168 8200-8204 Species denotes Mice Tax:10090
2169 9240-9244 Species denotes mice Tax:10090
2170 6649-6652 Chemical denotes HCQ MESH:D006886
2171 6729-6732 Chemical denotes HCQ MESH:D006886
2172 7395-7398 Chemical denotes HCQ MESH:D006886
2173 7796-7799 Chemical denotes HCQ MESH:D006886
2174 8345-8348 Chemical denotes HCQ MESH:D006886
2175 8449-8452 Chemical denotes HCQ MESH:D006886
2176 8801-8804 Chemical denotes HCQ MESH:D006886
2177 8930-8933 Chemical denotes HCQ MESH:D006886
2178 9431-9441 Chemical denotes trametinib MESH:C560077
2179 9602-9605 Chemical denotes HCQ MESH:D006886
2180 9629-9639 Chemical denotes trametinib MESH:C560077
2181 6811-6817 Disease denotes tumors MESH:D009369
2182 7174-7180 Disease denotes cancer MESH:D009369
2183 7530-7542 Disease denotes cytotoxicity MESH:D064420
2184 7546-7564 Disease denotes refractory cancers MESH:D009369
2185 7640-7646 Disease denotes cancer MESH:D009369
2186 7692-7697 Disease denotes tumor MESH:D009369
2187 8014-8019 Disease denotes tumor MESH:D009369
2188 8081-8113 Disease denotes pancreatic ductal adenocarcinoma MESH:D021441
2189 8125-8131 Disease denotes cancer MESH:D009369
2190 8144-8153 Disease denotes mortality MESH:D003643
2191 8322-8327 Disease denotes tumor MESH:D009369
2192 8467-8472 Disease denotes tumor MESH:D009369
2193 8633-8639 Disease denotes cancer MESH:D009369
2194 8691-8724 Disease denotes pancreatic ductal adenocarcinomas MESH:D021441
2195 8816-8821 Disease denotes tumor MESH:D009369
2196 8972-9004 Disease denotes pancreatic ductal adenocarcinoma MESH:D021441
2197 9342-9367 Disease denotes pancreatic carcinogenesis MESH:D063646
2198 9685-9710 Disease denotes reduction of tumor lesion MESH:D051437
2199 9729-9734 Disease denotes tumor MESH:D009369
2200 9747-9753 Disease denotes cancer MESH:D009369
2201 9765-9769 Disease denotes pain MESH:D010146
2242 10593-10610 Gene denotes estrogen receptor Gene:2099
2243 9826-9831 Species denotes human Tax:9606
2244 10762-10766 Species denotes mice Tax:10090
2245 10853-10857 Species denotes mice Tax:10090
2246 9892-9895 Chemical denotes HCQ MESH:D006886
2247 10156-10159 Chemical denotes HCQ MESH:D006886
2248 10193-10203 Chemical denotes Epirubicin MESH:D015251
2249 10423-10426 Chemical denotes HCQ MESH:D006886
2250 10674-10683 Chemical denotes tamoxifen MESH:D013629
2251 10746-10749 Chemical denotes HCQ MESH:D006886
2252 10779-10784 Chemical denotes water MESH:D014867
2253 10833-10842 Chemical denotes tamoxifen MESH:D013629
2254 10898-10901 Chemical denotes HCQ MESH:D006886
2255 11015-11018 Chemical denotes HCQ MESH:D006886
2256 11048-11059 Chemical denotes vemurafenib MESH:D000077484
2257 11164-11167 Chemical denotes HCQ MESH:D006886
2258 11183-11190 Chemical denotes CCI-779 MESH:C401859
2259 11367-11370 Chemical denotes HCQ MESH:D006886
2260 11610-11613 Chemical denotes HCQ MESH:D006886
2261 9780-9786 Disease denotes cancer MESH:D009369
2262 9802-9809 Disease denotes ovarian MESH:D010049
2263 9832-9845 Disease denotes breast cancer MESH:D001943
2264 9914-9919 Disease denotes tumor MESH:D009369
2265 10075-10081 Disease denotes cancer MESH:D009369
2266 10163-10169 Disease denotes cancer MESH:D009369
2267 10223-10236 Disease denotes breast cancer MESH:D001943
2268 10380-10386 Disease denotes cancer MESH:D009369
2269 10515-10520 Disease denotes tumor MESH:D009369
2270 10620-10634 Disease denotes breast cancers MESH:D001943
2271 10817-10823 Disease denotes cancer MESH:D009369
2272 10887-10896 Disease denotes carcinoma MESH:D009369
2273 10976-10981 Disease denotes tumor MESH:D009369
2274 11274-11288 Disease denotes melanoma tumor MESH:D008545
2275 11309-11314 Disease denotes tumor MESH:D009369
2276 11410-11436 Disease denotes chemoresistant lung cancer MESH:D008175
2277 11454-11460 Disease denotes cancer MESH:D009369
2278 11466-11473 Disease denotes hypoxic MESH:D000860
2279 11517-11523 Disease denotes cancer MESH:D009369
2280 11676-11681 Disease denotes tumor MESH:D009369
2281 11771-11776 Disease denotes tumor MESH:D009369
2289 12076-12080 Species denotes mice Tax:10090
2290 12119-12122 Chemical denotes HCQ MESH:D006886
2291 12172-12187 Chemical denotes 3-bromopyruvate MESH:C017092
2292 11965-11971 Disease denotes cancer MESH:D009369
2293 12051-12067 Disease denotes ascites hepatoma MESH:D001201
2294 12222-12227 Disease denotes tumor MESH:D009369
2295 12379-12385 Disease denotes cancer MESH:D009369
2380 12512-12517 Gene denotes Bcl-2 Gene:596
2381 12522-12528 Gene denotes Bcl-xL Gene:598
2382 12974-12979 Gene denotes Bcl-2 Gene:12043
2383 13319-13335 Gene denotes interferon-alpha Gene:111654
2384 13527-13543 Gene denotes interferon-alpha Gene:111654
2385 13696-13712 Gene denotes interferon-alpha Gene:111654
2386 14613-14621 Gene denotes Beclin 1 Gene:56208
2387 16022-16025 Gene denotes CA4 Gene:12351
2388 16166-16169 Gene denotes CA4 Gene:12351
2389 16840-16844 Gene denotes IL-6 Gene:3569
2390 15972-15975 Gene denotes CA4 Gene:12351
2391 12757-12761 Species denotes mice Tax:10090
2392 13074-13078 Species denotes mice Tax:10090
2393 13188-13192 Species denotes mice Tax:10090
2394 13633-13637 Species denotes mice Tax:10090
2395 14013-14018 Species denotes mouse Tax:10090
2396 14652-14658 Species denotes murine Tax:10090
2397 15180-15186 Species denotes humans Tax:9606
2398 15383-15388 Species denotes human Tax:9606
2399 15389-15394 Species denotes mouse Tax:10090
2400 15531-15535 Species denotes mice Tax:10090
2401 16136-16140 Species denotes mice Tax:10090
2402 17249-17257 Species denotes patients Tax:9606
2403 12652-12655 Chemical denotes HCQ MESH:D006886
2404 12700-12707 Chemical denotes ABT-737 MESH:C501332
2405 12860-12863 Chemical denotes HCQ MESH:D006886
2406 12867-12874 Chemical denotes ABT-737 MESH:C501332
2407 13016-13019 Chemical denotes HCQ MESH:D006886
2408 13718-13721 Chemical denotes HCQ MESH:D006886
2409 13746-13756 Chemical denotes wortmannin MESH:D000077191
2410 13914-13917 Chemical denotes HCQ MESH:D006886
2411 13969-13978 Chemical denotes melatonin MESH:D008550
2412 14054-14063 Chemical denotes melatonin MESH:D008550
2413 14251-14254 Chemical denotes HCQ MESH:D006886
2414 14273-14282 Chemical denotes melatonin MESH:D008550
2415 14634-14637 Chemical denotes HCQ MESH:D006886
2416 14950-14953 Chemical denotes HCQ MESH:D006886
2417 14974-14977 Chemical denotes HCQ MESH:D006886
2418 15102-15105 Chemical denotes HCQ MESH:D006886
2419 15213-15216 Chemical denotes HCQ MESH:D006886
2420 15280-15292 Chemical denotes chlorambucil MESH:D002699
2421 15479-15482 Chemical denotes HCQ MESH:D006886
2422 15487-15499 Chemical denotes chlorambucil MESH:D002699
2423 15682-15685 Chemical denotes HCQ MESH:D006886
2424 15770-15773 Chemical denotes HCQ MESH:D006886
2425 15876-15887 Chemical denotes doxorubicin MESH:D004317
2426 16052-16055 Chemical denotes HCQ MESH:D006886
2427 16305-16308 Chemical denotes HCQ MESH:D006886
2428 16333-16337 Chemical denotes iron MESH:D007501
2429 16348-16351 Chemical denotes ROS MESH:D017382
2430 16768-16771 Chemical denotes HCQ MESH:D006886
2431 16989-16999 Chemical denotes paclitaxel MESH:D017239
2432 17078-17081 Chemical denotes HCQ MESH:D006886
2433 17137-17140 Chemical denotes HCQ MESH:D006886
2434 12490-12505 Disease denotes β-Cell Lymphoma MESH:D016399
2435 12730-12746 Disease denotes prostatic cancer MESH:D011471
2436 13052-13065 Disease denotes neuroblastoma MESH:D009447
2437 13125-13130 Disease denotes tumor MESH:D009369
2438 13164-13174 Disease denotes metastases MESH:D009362
2439 13345-13351 Disease denotes cancer MESH:D009369
2440 13652-13675 Disease denotes neck squamous carcinoma MESH:D000077195
2441 13806-13811 Disease denotes tumor MESH:D009369
2442 13989-14012 Disease denotes squamous cell carcinoma MESH:D002294
2443 14327-14332 Disease denotes tumor MESH:D009369
2444 14391-14396 Disease denotes tumor MESH:D009369
2445 14669-14682 Disease denotes breast cancer MESH:D001943
2446 14937-14948 Disease denotes tumor death MESH:D003643
2447 15347-15371 Disease denotes leukemia/lymphoma cancer MESH:D009369
2448 15404-15422 Disease denotes Burkitt’s lymphoma MESH:D002051
2449 15608-15616 Disease denotes toxicity MESH:D064420
2450 15783-15788 Disease denotes tumor MESH:D009369
2451 15908-15916 Disease denotes melanoma MESH:D008545
2452 16070-16075 Disease denotes tumor MESH:D009369
2453 16121-16132 Disease denotes lung cancer MESH:D008175
2454 16292-16297 Disease denotes tumor MESH:D009369
2455 16470-16487 Disease denotes pancreatic cancer MESH:D010190
2456 16701-16717 Disease denotes liver metastases MESH:D009362
2457 16891-16897 Disease denotes cancer MESH:D009369
2458 16963-16978 Disease denotes stroma fibrosis MESH:D005355
2459 17020-17025 Disease denotes tumor MESH:D009369
2460 17094-17111 Disease denotes pancreatic cancer MESH:D010190
2461 17290-17307 Disease denotes pancreatic cancer MESH:D010190
2462 17344-17363 Disease denotes progressive disease MESH:D018450
2463 16116-16120 CellLine denotes A549 CVCL:0023
2474 17934-17938 Species denotes mice Tax:10090
2475 17618-17621 Chemical denotes HCQ MESH:D006886
2476 17814-17817 Chemical denotes HCQ MESH:D006886
2477 17852-17858 Chemical denotes ZD6474 MESH:C452423
2478 17973-17979 Chemical denotes ZD6474 MESH:C452423
2479 18074-18077 Chemical denotes HCQ MESH:D006886
2480 17530-17535 Disease denotes tumor MESH:D009369
2481 17683-17695 Disease denotes brain tumors MESH:D001932
2482 17919-17925 Disease denotes glioma MESH:D005910
2483 18127-18133 Disease denotes glioma MESH:D005910
2531 18274-18282 Species denotes patients Tax:9606
2532 18630-18637 Species denotes patient Tax:9606
2533 18883-18887 Species denotes mice Tax:10090
2534 19118-19126 Species denotes patients Tax:9606
2535 19430-19438 Species denotes patients Tax:9606
2536 19573-19581 Species denotes Patients Tax:9606
2537 19878-19886 Species denotes patients Tax:9606
2538 20005-20013 Species denotes patients Tax:9606
2539 20651-20659 Species denotes patients Tax:9606
2540 20731-20739 Species denotes patients Tax:9606
2541 18181-18184 Chemical denotes HCQ MESH:D006886
2542 18298-18310 Chemical denotes temozolomide MESH:D000077204
2543 18552-18555 Chemical denotes HCQ MESH:D006886
2544 18775-18778 Chemical denotes HCQ MESH:D006886
2545 18910-18913 Chemical denotes HCQ MESH:D006886
2546 19013-19016 Chemical denotes HCQ MESH:D006886
2547 19227-19239 Chemical denotes temsirolimus MESH:C401859
2548 19261-19264 Chemical denotes HCQ MESH:D006886
2549 19371-19374 Chemical denotes HCQ MESH:D006886
2550 19508-19520 Chemical denotes temozolomide MESH:D000077204
2551 19545-19548 Chemical denotes HCQ MESH:D006886
2552 19942-19945 Chemical denotes HCQ MESH:D006886
2553 20143-20146 Chemical denotes HCQ MESH:D006886
2554 20151-20161 Chemical denotes bortezomib MESH:D000069286
2555 20261-20264 Chemical denotes HCQ MESH:D006886
2556 20282-20292 Chemical denotes bortezomib MESH:D000069286
2557 20447-20450 Chemical denotes HCQ MESH:D006886
2558 20535-20545 Chemical denotes everolimus MESH:D000068338
2559 18261-18273 Disease denotes glioblastoma MESH:D005909
2560 18430-18435 Disease denotes tumor MESH:D009369
2561 18500-18508 Disease denotes toxicity MESH:D064420
2562 18673-18681 Disease denotes toxicity MESH:D064420
2563 18693-18709 Disease denotes myelosuppression MESH:D001855
2564 18711-18719 Disease denotes anorexia MESH:D000855
2565 18721-18728 Disease denotes fatigue MESH:D005221
2566 18733-18739 Disease denotes nausea MESH:D009325
2567 19138-19144 Disease denotes tumors MESH:D009369
2568 19159-19167 Disease denotes melanoma MESH:D008545
2569 19313-19318 Disease denotes tumor MESH:D009369
2570 19415-19423 Disease denotes toxicity MESH:D064420
2571 19455-19463 Disease denotes melanoma MESH:D008545
2572 19784-19794 Disease denotes toxicities MESH:D064420
2573 19892-19899 Disease denotes myeloma MESH:D009101
2574 20200-20207 Disease denotes myeloma MESH:D009101
2575 20398-20404 Disease denotes cancer MESH:D009369
2576 20487-20495 Disease denotes toxicity MESH:D064420
2577 20619-20650 Disease denotes clear-cell renal cell carcinoma MESH:C538614
2579 20765-20775 Disease denotes Infections MESH:D007239
2586 21073-21090 Species denotes Coxiella burnetii Tax:777
2587 21095-21114 Species denotes Tropheryma whipplei Tax:2039
2588 20776-20779 Chemical denotes HCQ MESH:D006886
2589 20929-20932 Chemical denotes HCQ MESH:D006886
2590 21002-21013 Chemical denotes doxycycline MESH:D004318
2591 20852-20860 Disease denotes infected MESH:D007239
2653 23448-23451 Gene denotes DCX Gene:1641
2654 21116-21127 Species denotes C. burnetii Tax:777
2655 21312-21317 Species denotes human Tax:9606
2656 21735-21746 Species denotes C. burnetii Tax:777
2657 21892-21900 Species denotes patients Tax:9606
2658 21967-21978 Species denotes C. burnetii Tax:777
2659 22581-22585 Species denotes girl Tax:9606
2660 23191-23202 Species denotes C. burnetii Tax:777
2661 23270-23278 Species denotes patients Tax:9606
2662 23758-23766 Species denotes patients Tax:9606
2663 22680-22691 Species denotes C. burnetii Tax:777
2664 22098-22109 Chemical denotes doxycycline MESH:D004318
2665 22111-22114 Chemical denotes DXC MESH:D004318
2666 22224-22227 Chemical denotes HCQ MESH:D006886
2667 22253-22256 Chemical denotes HCQ MESH:D006886
2668 22357-22368 Chemical denotes doxycycline MESH:D004318
2669 22472-22475 Chemical denotes DXC MESH:D004318
2670 22480-22483 Chemical denotes HCQ MESH:D006886
2671 22626-22629 Chemical denotes DXC MESH:D004318
2672 22648-22651 Chemical denotes HCQ MESH:D006886
2673 22790-22793 Chemical denotes DXC MESH:D004318
2674 22818-22821 Chemical denotes HCQ MESH:D006886
2675 22974-22977 Chemical denotes DXC MESH:D004318
2676 22990-22999 Chemical denotes ofloxacin MESH:D015242
2677 23089-23092 Chemical denotes DXC MESH:D004318
2678 23098-23101 Chemical denotes HCQ MESH:D006886
2679 23457-23460 Chemical denotes HCQ MESH:D006886
2680 23707-23710 Chemical denotes DXC MESH:D004318
2681 23715-23718 Chemical denotes HCQ MESH:D006886
2682 23945-23948 Chemical denotes DXC MESH:D004318
2683 23953-23956 Chemical denotes HCQ MESH:D006886
2684 24228-24231 Chemical denotes DXC MESH:D004318
2685 24302-24305 Chemical denotes DXC MESH:D004318
2686 24330-24333 Chemical denotes HCQ MESH:D006886
2687 21205-21210 Disease denotes fever MESH:D005334
2688 21214-21219 Disease denotes fever MESH:D005334
2689 21226-21235 Disease denotes infection MESH:D007239
2690 21276-21284 Disease denotes infected MESH:D007239
2691 21359-21364 Disease denotes fever MESH:D005334
2692 21476-21485 Disease denotes infection MESH:D007239
2693 21624-21639 Disease denotes febrile illness MESH:D005334
2694 21641-21648 Disease denotes myalgia MESH:D063806
2695 21650-21658 Disease denotes headache MESH:D006261
2696 21677-21686 Disease denotes hepatitis MESH:D056486
2697 21692-21701 Disease denotes pneumonia MESH:D011014
2698 21747-21757 Disease denotes infections MESH:D007239
2699 21805-21840 Disease denotes endocarditis and vascular infection MESH:D004696
2700 21873-21878 Disease denotes fever MESH:D005334
2701 21919-21937 Disease denotes vascular disorders MESH:D000783
2702 21941-21955 Disease denotes valvulopathies MESH:D006349
2703 22439-22457 Disease denotes fever endocarditis MESH:D005334
2704 22572-22580 Disease denotes infected MESH:D007239
2705 23048-23056 Disease denotes infected MESH:D007239
2706 23284-23296 Disease denotes valvulopathy MESH:D006349
2707 23324-23329 Disease denotes fever MESH:D005334
2708 23525-23543 Disease denotes fever endocarditis MESH:D005334
2709 23644-23662 Disease denotes fever endocarditis MESH:D005334
2710 24042-24062 Disease denotes abnormal weight gain MESH:D015430
2711 24077-24089 Disease denotes erythroderma MESH:D003873
2712 24095-24116 Disease denotes impaired visual field MESH:D005128
2713 24182-24191 Disease denotes infection MESH:D007239
2744 25593-25596 Gene denotes DCX Gene:1641
2745 25647-25650 Gene denotes DCX Gene:1641
2746 25793-25796 Gene denotes DCX Gene:1641
2747 26085-26088 Gene denotes DCX Gene:1641
2748 24500-24511 Species denotes T. whipplei Tax:2039
2749 24597-24608 Species denotes T. whipplei Tax:2039
2750 24616-24621 Species denotes human Tax:9606
2751 24990-24998 Species denotes patients Tax:9606
2752 25149-25160 Species denotes T. whipplei Tax:2039
2753 25521-25532 Species denotes C. burnetii Tax:777
2754 25604-25615 Species denotes T. whipplei Tax:2039
2755 25667-25678 Species denotes T. whipplei Tax:2039
2756 25822-25830 Species denotes patients Tax:9606
2757 25191-25224 Chemical denotes trimethoprim and sulfamethoxazole
2758 25316-25328 Chemical denotes trimethoprim MESH:D014295
2759 25373-25389 Chemical denotes sulfamethoxazole MESH:D013420
2760 25597-25600 Chemical denotes HCQ MESH:D006886
2761 25812-25815 Chemical denotes HCQ MESH:D006886
2762 26064-26067 Chemical denotes HCQ MESH:D006886
2763 26175-26178 Chemical denotes DXC MESH:D004318
2764 26247-26258 Chemical denotes ceftriaxone MESH:D002443
2765 24557-24574 Disease denotes Whipple’s disease MESH:D008061
2766 24746-24755 Disease denotes infection MESH:D007239
2767 24819-24827 Disease denotes diarrhea MESH:D003967
2768 24844-24857 Disease denotes malabsorption MESH:D008286
2769 24863-24874 Disease denotes weight loss MESH:D015431
2770 24894-24907 Disease denotes Joint disease MESH:D007592
2771 25036-25053 Disease denotes cardiac disorders MESH:D006331
2772 25093-25110 Disease denotes Whipple’s disease MESH:D008061
2773 25533-25543 Disease denotes infections MESH:D007239
2777 26386-26389 Chemical denotes HCQ MESH:D006886
2778 26565-26568 Chemical denotes HCQ MESH:D006886
2779 26427-26447 Disease denotes bacterial infections MESH:D001424

LitCovid-PD-HP

Id Subject Object Predicate Lexical cue hp_id
T122 281-300 Phenotype denotes Autoimmune Diseases http://purl.obolibrary.org/obo/HP_0002960
T123 491-511 Phenotype denotes rheumatoid arthritis http://purl.obolibrary.org/obo/HP_0001370
T124 637-657 Phenotype denotes rheumatoid arthritis http://purl.obolibrary.org/obo/HP_0001370
T125 892-912 Phenotype denotes rheumatoid arthritis http://purl.obolibrary.org/obo/HP_0001370
T126 1594-1614 Phenotype denotes rheumatoid arthritis http://purl.obolibrary.org/obo/HP_0001370
T127 2895-2915 Phenotype denotes rheumatoid arthritis http://purl.obolibrary.org/obo/HP_0001370
T128 3521-3550 Phenotype denotes juvenile idiopathic arthritis http://purl.obolibrary.org/obo/HP_0005681
T129 3777-3797 Phenotype denotes rheumatoid arthritis http://purl.obolibrary.org/obo/HP_0001370
T130 3857-3875 Phenotype denotes autoimmune disease http://purl.obolibrary.org/obo/HP_0002960
T131 5666-5689 Phenotype denotes cardiovascular diseases http://purl.obolibrary.org/obo/HP_0001626
T132 5946-5964 Phenotype denotes myocardial infarct http://purl.obolibrary.org/obo/HP_0001658
T133 6160-6174 Phenotype denotes cardiomyopathy http://purl.obolibrary.org/obo/HP_0001638
T134 6188-6194 Phenotype denotes stroke http://purl.obolibrary.org/obo/HP_0001297
T135 7174-7180 Phenotype denotes cancer http://purl.obolibrary.org/obo/HP_0002664
T136 7263-7278 Phenotype denotes drug resistance http://purl.obolibrary.org/obo/HP_0020174
T137 7640-7646 Phenotype denotes cancer http://purl.obolibrary.org/obo/HP_0002664
T138 7692-7697 Phenotype denotes tumor http://purl.obolibrary.org/obo/HP_0002664
T139 8014-8019 Phenotype denotes tumor http://purl.obolibrary.org/obo/HP_0002664
T140 8125-8131 Phenotype denotes cancer http://purl.obolibrary.org/obo/HP_0002664
T141 8322-8327 Phenotype denotes tumor http://purl.obolibrary.org/obo/HP_0002664
T142 8467-8472 Phenotype denotes tumor http://purl.obolibrary.org/obo/HP_0002664
T143 8633-8639 Phenotype denotes cancer http://purl.obolibrary.org/obo/HP_0002664
T144 8816-8821 Phenotype denotes tumor http://purl.obolibrary.org/obo/HP_0002664
T145 9698-9703 Phenotype denotes tumor http://purl.obolibrary.org/obo/HP_0002664
T146 9729-9734 Phenotype denotes tumor http://purl.obolibrary.org/obo/HP_0002664
T147 9747-9753 Phenotype denotes cancer http://purl.obolibrary.org/obo/HP_0002664
T148 9765-9769 Phenotype denotes pain http://purl.obolibrary.org/obo/HP_0012531
T149 9780-9786 Phenotype denotes cancer http://purl.obolibrary.org/obo/HP_0002664
T150 9832-9845 Phenotype denotes breast cancer http://purl.obolibrary.org/obo/HP_0003002
T151 9914-9919 Phenotype denotes tumor http://purl.obolibrary.org/obo/HP_0002664
T152 10075-10081 Phenotype denotes cancer http://purl.obolibrary.org/obo/HP_0002664
T153 10163-10169 Phenotype denotes cancer http://purl.obolibrary.org/obo/HP_0002664
T154 10223-10236 Phenotype denotes breast cancer http://purl.obolibrary.org/obo/HP_0003002
T155 10380-10386 Phenotype denotes cancer http://purl.obolibrary.org/obo/HP_0002664
T156 10515-10520 Phenotype denotes tumor http://purl.obolibrary.org/obo/HP_0002664
T157 10620-10634 Phenotype denotes breast cancers http://purl.obolibrary.org/obo/HP_0003002
T158 10817-10823 Phenotype denotes cancer http://purl.obolibrary.org/obo/HP_0002664
T159 10887-10896 Phenotype denotes carcinoma http://purl.obolibrary.org/obo/HP_0030731
T160 10976-10981 Phenotype denotes tumor http://purl.obolibrary.org/obo/HP_0002664
T161 11274-11282 Phenotype denotes melanoma http://purl.obolibrary.org/obo/HP_0002861
T162 11283-11288 Phenotype denotes tumor http://purl.obolibrary.org/obo/HP_0002664
T163 11309-11314 Phenotype denotes tumor http://purl.obolibrary.org/obo/HP_0002664
T164 11425-11436 Phenotype denotes lung cancer http://purl.obolibrary.org/obo/HP_0100526
T165 11454-11460 Phenotype denotes cancer http://purl.obolibrary.org/obo/HP_0002664
T166 11517-11523 Phenotype denotes cancer http://purl.obolibrary.org/obo/HP_0002664
T167 11676-11681 Phenotype denotes tumor http://purl.obolibrary.org/obo/HP_0002664
T168 11771-11776 Phenotype denotes tumor http://purl.obolibrary.org/obo/HP_0002664
T169 11965-11971 Phenotype denotes cancer http://purl.obolibrary.org/obo/HP_0002664
T170 12051-12058 Phenotype denotes ascites http://purl.obolibrary.org/obo/HP_0001541
T171 12222-12227 Phenotype denotes tumor http://purl.obolibrary.org/obo/HP_0002664
T172 12379-12385 Phenotype denotes cancer http://purl.obolibrary.org/obo/HP_0002664
T173 12497-12505 Phenotype denotes Lymphoma http://purl.obolibrary.org/obo/HP_0002665
T174 12730-12746 Phenotype denotes prostatic cancer http://purl.obolibrary.org/obo/HP_0012125
T175 12775-12780 Phenotype denotes Tumor http://purl.obolibrary.org/obo/HP_0002664
T176 13052-13065 Phenotype denotes neuroblastoma http://purl.obolibrary.org/obo/HP_0003006
T177 13125-13130 Phenotype denotes tumor http://purl.obolibrary.org/obo/HP_0002664
T178 13345-13351 Phenotype denotes cancer http://purl.obolibrary.org/obo/HP_0002664
T179 13666-13675 Phenotype denotes carcinoma http://purl.obolibrary.org/obo/HP_0030731
T180 13806-13811 Phenotype denotes tumor http://purl.obolibrary.org/obo/HP_0002664
T181 13989-14012 Phenotype denotes squamous cell carcinoma http://purl.obolibrary.org/obo/HP_0002860
T182 14327-14332 Phenotype denotes tumor http://purl.obolibrary.org/obo/HP_0002664
T183 14391-14396 Phenotype denotes tumor http://purl.obolibrary.org/obo/HP_0002664
T184 14669-14682 Phenotype denotes breast cancer http://purl.obolibrary.org/obo/HP_0003002
T185 14937-14942 Phenotype denotes tumor http://purl.obolibrary.org/obo/HP_0002664
T186 15347-15355 Phenotype denotes leukemia http://purl.obolibrary.org/obo/HP_0001909
T187 15356-15364 Phenotype denotes lymphoma http://purl.obolibrary.org/obo/HP_0002665
T188 15365-15371 Phenotype denotes cancer http://purl.obolibrary.org/obo/HP_0002664
T189 15404-15422 Phenotype denotes Burkitt’s lymphoma http://purl.obolibrary.org/obo/HP_0030080
T190 15783-15788 Phenotype denotes tumor http://purl.obolibrary.org/obo/HP_0002664
T191 15908-15916 Phenotype denotes melanoma http://purl.obolibrary.org/obo/HP_0002861
T192 16070-16075 Phenotype denotes tumor http://purl.obolibrary.org/obo/HP_0002664
T193 16121-16132 Phenotype denotes lung cancer http://purl.obolibrary.org/obo/HP_0100526
T194 16292-16297 Phenotype denotes tumor http://purl.obolibrary.org/obo/HP_0002664
T195 16470-16487 Phenotype denotes pancreatic cancer http://purl.obolibrary.org/obo/HP_0002894
T196 16659-16664 Phenotype denotes Tumor http://purl.obolibrary.org/obo/HP_0002664
T197 16891-16897 Phenotype denotes cancer http://purl.obolibrary.org/obo/HP_0002664
T198 17020-17025 Phenotype denotes tumor http://purl.obolibrary.org/obo/HP_0002664
T199 17094-17111 Phenotype denotes pancreatic cancer http://purl.obolibrary.org/obo/HP_0002894
T200 17290-17307 Phenotype denotes pancreatic cancer http://purl.obolibrary.org/obo/HP_0002894
T201 17530-17535 Phenotype denotes tumor http://purl.obolibrary.org/obo/HP_0002664
T202 17683-17695 Phenotype denotes brain tumors http://purl.obolibrary.org/obo/HP_0030692
T203 17919-17925 Phenotype denotes glioma http://purl.obolibrary.org/obo/HP_0009733
T204 18127-18133 Phenotype denotes glioma http://purl.obolibrary.org/obo/HP_0009733
T205 18261-18273 Phenotype denotes glioblastoma http://purl.obolibrary.org/obo/HP_0012174
T206 18430-18435 Phenotype denotes tumor http://purl.obolibrary.org/obo/HP_0002664
T207 18711-18719 Phenotype denotes anorexia http://purl.obolibrary.org/obo/HP_0002039
T208 18721-18728 Phenotype denotes fatigue http://purl.obolibrary.org/obo/HP_0012378
T209 18733-18739 Phenotype denotes nausea http://purl.obolibrary.org/obo/HP_0002018
T210 19159-19167 Phenotype denotes melanoma http://purl.obolibrary.org/obo/HP_0002861
T211 19313-19318 Phenotype denotes tumor http://purl.obolibrary.org/obo/HP_0002664
T212 19455-19463 Phenotype denotes melanoma http://purl.obolibrary.org/obo/HP_0002861
T213 20375-20394 Phenotype denotes autophagic vacuoles http://purl.obolibrary.org/obo/HP_0003736
T214 20398-20404 Phenotype denotes cancer http://purl.obolibrary.org/obo/HP_0002664
T215 20619-20650 Phenotype denotes clear-cell renal cell carcinoma http://purl.obolibrary.org/obo/HP_0006770
T216 21205-21210 Phenotype denotes fever http://purl.obolibrary.org/obo/HP_0001945
T217 21214-21219 Phenotype denotes fever http://purl.obolibrary.org/obo/HP_0001945
T218 21359-21364 Phenotype denotes fever http://purl.obolibrary.org/obo/HP_0001945
T219 21468-21485 Phenotype denotes chronic infection http://purl.obolibrary.org/obo/HP_0031035
T220 21641-21648 Phenotype denotes myalgia http://purl.obolibrary.org/obo/HP_0003326
T221 21650-21658 Phenotype denotes headache http://purl.obolibrary.org/obo/HP_0002315
T222 21660-21666 Phenotype denotes chills http://purl.obolibrary.org/obo/HP_0025143
T223 21677-21686 Phenotype denotes hepatitis http://purl.obolibrary.org/obo/HP_0012115
T224 21692-21701 Phenotype denotes pneumonia http://purl.obolibrary.org/obo/HP_0002090
T225 21805-21817 Phenotype denotes endocarditis http://purl.obolibrary.org/obo/HP_0100584
T226 21873-21878 Phenotype denotes fever http://purl.obolibrary.org/obo/HP_0001945
T227 22439-22444 Phenotype denotes fever http://purl.obolibrary.org/obo/HP_0001945
T228 22445-22457 Phenotype denotes endocarditis http://purl.obolibrary.org/obo/HP_0100584
T229 23324-23329 Phenotype denotes fever http://purl.obolibrary.org/obo/HP_0001945
T230 23525-23530 Phenotype denotes fever http://purl.obolibrary.org/obo/HP_0001945
T231 23531-23543 Phenotype denotes endocarditis http://purl.obolibrary.org/obo/HP_0100584
T232 23644-23649 Phenotype denotes fever http://purl.obolibrary.org/obo/HP_0001945
T233 23650-23662 Phenotype denotes endocarditis http://purl.obolibrary.org/obo/HP_0100584
T234 24018-24034 Phenotype denotes photosensitivity http://purl.obolibrary.org/obo/HP_0000992
T235 24051-24062 Phenotype denotes weight gain http://purl.obolibrary.org/obo/HP_0004324
T236 24077-24089 Phenotype denotes erythroderma http://purl.obolibrary.org/obo/HP_0001019
T237 24819-24827 Phenotype denotes diarrhea http://purl.obolibrary.org/obo/HP_0002014
T238 24844-24857 Phenotype denotes malabsorption http://purl.obolibrary.org/obo/HP_0002024
T239 24863-24874 Phenotype denotes weight loss http://purl.obolibrary.org/obo/HP_0001824
T240 24894-24907 Phenotype denotes Joint disease http://purl.obolibrary.org/obo/HP_0001367

LitCovid-sentences

Id Subject Object Predicate Lexical cue
T422 0-4 Sentence denotes 2.4.
T423 5-43 Sentence denotes Hydroxychloroquine and Synergic Effect
T424 44-272 Sentence denotes The choice of HCQ as an additive therapy in many medical regimens is due to the synergistic effect that enhances the efficacy of other drugs in the treatment of several diseases that have been frequently demonstrated as follows.
T425 274-280 Sentence denotes 2.4.1.
T426 281-300 Sentence denotes Autoimmune Diseases
T427 301-518 Sentence denotes HCQ belongs to the group of the disease-modifying antirheumatic drug (DMARD), which comprises drugs that are not chemically relted, sharing the same efficacy in dampening the progression of rheumatoid arthritis [122].
T428 519-664 Sentence denotes It often occurs also that glucocorticoids or natural antioxidant substances are included in the coadjutant therapy of rheumatoid arthritis [123].
T429 665-927 Sentence denotes A multicenter, randomized clinical trial analyzed the tolerability and the efficacy of combined therapy, including HCQ, sulphasalazine, MXT, and PRD with respect to the use of a single antirheumatic drug in the caring of early rheumatoid arthritis for two years.
T430 928-1033 Sentence denotes A total of 195 patients were equally divided into two groups to follow the assigned therapeutic protocol.
T431 1034-1262 Sentence denotes The primary aim of clinical remission was achieved after one year by 24 of the 97 patients under combinatory therapy, while only by 11 of 98 single-drug therapy users, but this trend was further confirmed during the second year.
T432 1263-1423 Sentence denotes After one year, 75% of subjects under combinatory therapy and 60% of those under single-therapy reached clinical improvement, intended as 50% clinical response.
T433 1424-1538 Sentence denotes In terms of tolerability, the cotreatment resulted not to be more dangerous with respect to the single drug [123].
T434 1539-1742 Sentence denotes In a prospective trial, patients with the diagnosis of rheumatoid arthritis were scheduled to receive cotreatment of sulphasalazine (1–3 g/day), MXT (7.5–15 mg/week), and HCQ (200 mg/day) for six months.
T435 1743-1868 Sentence denotes Significant improvements in clinical parameters revealed the efficacy of the cotreatment in counteracting endothelial injury.
T436 1869-2038 Sentence denotes Indeed, the blood concentrations of endothelial injury markers, mainly soluble E selectin and thrombomodulin, experienced a significant drop after the cotreatment [124].
T437 2039-2430 Sentence denotes Likewise, a single-blinded clinical trial on 281 patients confirmed the better therapeutic efficiency of cotreatment (25 mg/week MXT, 2 g/day of sulphasalazine, and 400 mg/day HCQ p.o. plus intramuscular injection (i.m.) doses of 120 mg of methylprednisolone or 80 mg of triamcinolone) with respect to single therapy after three months, without significant differences in side effects [125].
T438 2431-2790 Sentence denotes Proofs of the better antirheumatic potential of the combination of drugs with respect to single therapy derived from an observational study that evaluated the higher improvement of quality of patients’ life after one year of coadministration of MXT, HCQ, and corticosteroids with respect to single MXT, or HCQ, or their combination with corticosteroids [126].
T439 2791-3009 Sentence denotes Great insights in disease remission were provided by a clinical trial involving 17 patients with active rheumatoid arthritis where the chronic inflammatory status of joints was evaluated through the 18F-FDG PET method.
T440 3010-3281 Sentence denotes It was found that cotreatment with 7.5–15 mg/week of MXT, 2 g/day of sulphasalazine, 5 mg/kg/day of HCQ and a low dose of oral PRD (under 10 mg/day) is associated with a reduction of 30% in 18F-FDG uptake measures on PET imaging in 81% of patients after four weeks [127].
T441 3282-3388 Sentence denotes Although HCQ is effective and well-tolerated, other therapeutic alternatives have emerged in recent years.
T442 3389-3446 Sentence denotes Among them, monoclonal antibodies are the most promising.
T443 3447-3761 Sentence denotes In a multicenter open-label clinical trial, performed on 60 patients with juvenile idiopathic arthritis for 54 weeks, the combination of infliximab monoclonal antibodies with a conventional antirheumatic drug provided the better response in terms of disease inactivation with respect to DMARD administration [128].
T444 3762-3876 Sentence denotes In addition to rheumatoid arthritis patients, HCQ is also used in lupus erythematosus, another autoimmune disease.
T445 3877-3927 Sentence denotes Regarding lupus erythematosus, HCQ is widely used.
T446 3928-4267 Sentence denotes In vivo studies on a NZB/W F1 murine model of lupus showed that HCQ in combination with PRD (2.5 mg/kg/day and 1 mg/kg/day p.o.) decreased autoantibody production, as well as being able to inhibit toll-like receptor activation, resulting in the down-regulation of type I interferon (IFN-α) which is deeply implicated in lupus pathogenesis.
T447 4268-4576 Sentence denotes The efficacy of treatment is due to the ability of drugs to alter the expression of urinary and immune cell micro RNA that contribute to lupus progression by post-transcriptional modulation of genes involved in the immune response, pro-inflammatory cytokines production and toll-like receptor pathways [129].
T448 4577-4683 Sentence denotes In association with low-dose aspirin, HCQ is also indicated for thromboprophylaxis in patients with lupus.
T449 4684-4978 Sentence denotes The occurrence of thrombotic events was recorded for 13 years in 189 patients, showing that the cardiovascular complications were more frequent in patients treated only with aspirin, while HCQ (up to 600 mg) was associated with a stronger thrombo-protective effect in patients with lupus [130].
T450 4979-5128 Sentence denotes Thanks to its immunomodulatory properties, HCQ (20 mg/kg) was revealed to be useful in graft-versus-host disease, in combination with cyclosporine A.
T451 5129-5236 Sentence denotes They synergistically suppressed T cell response, allowing the reduction of the dose of drugs in mice [131].
T452 5238-5244 Sentence denotes 2.4.2.
T453 5245-5275 Sentence denotes Cardiovascular Risk Management
T454 5276-5405 Sentence denotes HCQ revealed the great potential in the management of cardiovascular risk by controlling glucose homeostasis and lipidic profile.
T455 5406-5544 Sentence denotes Until now, in this review, we discussed the effect of HCQ alone to counteract cardiovascular complications, mostly in autoimmune patients.
T456 5545-5690 Sentence denotes Here, we reviewed the multiple pleiotropic actions of HCQ in combination with conventional medication in the most common cardiovascular diseases.
T457 5691-5910 Sentence denotes The cardioprotective effects of one week of treatment with 50 mg/kg of HCQ i.g. against ischemia-reperfusion injury in type-2 diabetic mice were assessed in combination with the phosphodiesterase-5 inhibitor, tadalafil.
T458 5911-6036 Sentence denotes The synergistic effect reduced the myocardial infarct size by up to 20% and improved insulin secretion and sensitivity [132].
T459 6037-6249 Sentence denotes Moreover, low-dose HCQ (3.4 mg/kg/day) prevented cardiomyocyte apoptosis in the periinfarct myocardium, dampening ischemic cardiomyopathy, and cardiac stroke, as demonstrated by Jalal, et al. [133] in rat models.
T460 6250-6386 Sentence denotes The role of HCQ in the inhibition of platelet aggregation was evaluated in healthy volunteers in comparison with aspirin or clopidogrel.
T461 6387-6499 Sentence denotes The addition of 400 mg/day of HCQ to aspirin resulted in a significant increase in aggregation inhibition (31%).
T462 6500-6629 Sentence denotes This inhibition was passed by reducing fibrinogen and inflammatory status by interfering with the arachidonic acid cascade [134].
T463 6631-6637 Sentence denotes 2.4.3.
T464 6638-6648 Sentence denotes Anticancer
T465 6649-6728 Sentence denotes HCQ explains its antitumor activity thanks to its ability to inhibit autophagy.
T466 6729-6793 Sentence denotes HCQ is, indeed, an FDA-approved drug inhibiting autophagy [135].
T467 6794-6871 Sentence denotes Several types of tumors develop chemoresistance by enhancing autophagic flux.
T468 6872-7054 Sentence denotes Autophagy consists in the sequestration of materials in autophagic vesicles to be eliminated through lysosomal fusion and allows cells to overcome metabolic and therapeutic stresses.
T469 7055-7157 Sentence denotes By recycling intracellular components, cells may maintain an energy balance and increase their growth.
T470 7158-7224 Sentence denotes If it occurs in cancer cells, resistance mechanisms may establish.
T471 7225-7368 Sentence denotes One of the mechanisms responsible for drug resistance is related to increased drug efflux by ATP-binding cassette (ABC) transporters [136,137].
T472 7369-7605 Sentence denotes It has been observed that HCQ is significantly reduced the increase in P-gp (ABCB1) expression and, in combination with several anticancer drugs, induced higher cytotoxicity in refractory cancers by inhibiting autophagic activity [138].
T473 7606-7722 Sentence denotes However, the role of autophagy in cancer is controversial and depends on genotype and tumor stage development [139].
T474 7723-7920 Sentence denotes Many clinical trials examined the synergistic effects of the addition of HCQ to conventional chemotherapic drugs, finding that the role of autophagy is complex and is influenced by several factors.
T475 7921-8038 Sentence denotes Depending on genetic concomitant alterations, autophagy may possess both pro-tumorigenic and tumor-suppressive roles.
T476 8039-8199 Sentence denotes It has been confirmed in murine models of pancreatic ductal adenocarcinoma, a type of cancer with a high mortality rate, due to its refractoriness to therapies.
T477 8200-8369 Sentence denotes Mice presenting activated oncogenic KRAS and normal expression of p53 oncosuppressor experienced a critical regression of tumor developing under HCQ (60 mg/kg/day i.p.).
T478 8370-8590 Sentence denotes By contrast, in those with a deficiency of p53, the inhibition of autophagy by HCQ increased the tumor progression, demonstrating that autophagy’s role in tumorigenesis is strictly related to the expression of p53 [140].
T479 8591-8731 Sentence denotes The expression of p53 is often altered in cancer, so as to be found mutated or absent in the 75% of pancreatic ductal adenocarcinomas [141].
T480 8732-8828 Sentence denotes This issue highlights the necessity to carefully evaluate the use of HCQ in certain tumor types.
T481 8829-9054 Sentence denotes Different outcomes have been previously described, it has been found that inhibition of autophagy by HCQ might arise as a valuable adjuvant in pancreatic ductal adenocarcinoma chemotherapy, regardless of p53 status [142,143].
T482 9055-9259 Sentence denotes Given the same doses and route of administration, these inconsistencies between the two reported studies could probably derive from the use of p53 homozygous and heterozygous models of mice, respectively.
T483 9260-9368 Sentence denotes Regarding KRAS oncoprotein, its downstream pathway is one of the major players of pancreatic carcinogenesis.
T484 9369-9493 Sentence denotes The inhibition of this pathway by cytotoxic drugs, as well as trametinib, is often associated with an increase in autophagy.
T485 9494-9770 Sentence denotes For this reason, Drucker and Rosen [144] performed an off-label trial with an association of 400–1200 mg of HCQ and a constant dose of trametinib, observing a partial response with a general reduction of tumor lesion size, circulating tumor markers and cancer-associated pain.
T486 9771-9926 Sentence denotes In other cancer types, such as ovarian, prostatic, and human breast cancer, the anticancer or pro-tumorigenic effects of HCQ are determined by tumor stage.
T487 9927-10097 Sentence denotes In the early stages of the disease, the inhibition of autophagy results in an inhibition of tumorigenesis, while in the advanced phase, it enhances cancer survival [145].
T488 10098-10192 Sentence denotes Then, it is important in assessing the contextual role of HCQ in cancer resistance mechanisms.
T489 10193-10299 Sentence denotes Epirubicin in triple-negative breast cancer therapy often lost efficacy, due to chemoresistance acquiring.
T490 10300-10401 Sentence denotes It has been shown that this cytotoxic agent induced autophagic flux, increasing cancer cell survival.
T491 10402-10579 Sentence denotes The combination with HCQ (120 mg/kg by i.p.), thanks to the anti-autophagic properties, significantly suppressed tumor growth by up to 50% with respect to the monotherapy [142].
T492 10580-10721 Sentence denotes In addition, estrogen receptor-positive breast cancers developed resistance to treatment with tamoxifen, due to the enhancement of autophagy.
T493 10722-10849 Sentence denotes The coadministration of HCQ (1–2 mg/day/mice in drinking water) restored the susceptibility of cancer cells to tamoxifen [146].
T494 10850-11118 Sentence denotes In mice with thyroid gland xenograft carcinoma, HCQ (150 mg/kg/day p.o. for two weeks) did not provide significant results on tumor growth, while the combination of HCQ with the chemotherapic agent vemurafenib potentiated the anticancer properties of both drugs [147].
T495 11119-11366 Sentence denotes Similarly, the two weeks coadministration of HCQ (65 mg/kg) and CCI-779 resulted in a synergism that significantly enhanced their in vivo activity against melanoma tumor growth, in terms of tumor size, with respect to their single treatment [148].
T496 11367-11437 Sentence denotes HCQ was revealed also to be active against chemoresistant lung cancer.
T497 11438-11609 Sentence denotes In this type of cancer, the hypoxic conditions led to lesser susceptibility of cancer cells towards lymphocyte T-mediated cytolysis, thanks to the activation of autophagy.
T498 11610-11783 Sentence denotes HCQ intake, at doses of 30 mg/kg/day i.p. for 10 days, sensitized tumor cells to lysis and allowed, together with conventional treatment, the eradication of the tumor [149].
T499 11784-11886 Sentence denotes Together with autophagy, glycolysis plays a pivotal role in satisfying the increased energetic demand.
T500 11887-11978 Sentence denotes The dual targeting of the processes may provide a new therapeutic approach in cancer cells.
T501 11979-12246 Sentence denotes Emonet, et al. [150] performed a randomized preclinical study on Earlic ascites hepatoma-bearing mice, showing that the coadministration of HCQ (60 mg/kg i.p.) and the antiglycolytic inhibitor 3-bromopyruvate possessed a synergistic effect on tumor growth inhibition.
T502 12247-12438 Sentence denotes Moreover, this treatment is associated with an improvement of oxidative status in hepatic tissue, with a decrement in the number of cancer cells, without affecting the total cell count [151].
T503 12439-12564 Sentence denotes Resistance mechanisms also involved alterations in β-Cell Lymphoma (Bcl) Bcl-2 and Bcl-xL and anti-apoptotic gene expression.
T504 12565-12774 Sentence denotes To evaluate the validity of the dual approach, targeting both apoptosis and autophagy, HCQ (50 mg/kg i.p.) and an apoptosis inhibitor, ABT-737, were administered to prostatic cancer xenograft mice for 15 days.
T505 12775-12887 Sentence denotes Tumor growth was significantly suppressed by a combination of drugs, with respect to HCQ or ABT-737 alone [152].
T506 12888-13079 Sentence denotes In the same way, Fenollar, et al. [153] demonstrated the efficacy of Obatoclax, a pan-Bcl-2 inhibitor, used in association with HCQ (3–60 mg/kg) or conventional in neuroblastoma-bearing mice.
T507 13080-13258 Sentence denotes Positive outcomes regarded the diminution of tumor size and the complete absence of metastases in cotreated mice with respect to Obatoclax alone or with respect to control [154].
T508 13259-13414 Sentence denotes Apoptosis is also at the base of the anticancer activity of interferon-alpha, but the cancer treatment with this drug alone often leads to chemoresistance.
T509 13415-13616 Sentence denotes It has been demonstrated that autophagy is in the main responsible for chemoresistance, thus the combination of interferon-alpha with inhibitors of autophagic flux may be a useful therapeutic approach.
T510 13617-13825 Sentence denotes In 30 xenograft mice with head and neck squamous carcinoma, the combination of interferon-alpha with HCQ (60 mg/kg/day i.g.) and wortmannin synergistically promoted apoptosis and inhibited tumor growth [155].
T511 13826-14026 Sentence denotes In a similar fashion, Le Goff, et al. [156] investigated the potential synergic role of HCQ (30 mg/kg) in enhancing the anticancer activity of melatonin on tongue squamous cell carcinoma mouse models.
T512 14027-14101 Sentence denotes The anticancer activity of melatonin depends on its pro-apoptotic effects.
T513 14102-14202 Sentence denotes Nevertheless, this activity is accompanied by a pro-autophagic activity that caused chemoresistance.
T514 14203-14349 Sentence denotes The coadministration of the autophagy inhibitor HCQ strongly enhanced melatonin anticancer efficacy, resulting in a smaller tumor size and weight.
T515 14350-14513 Sentence denotes The effect of inhibition of autophagy on tumor growth may be enhanced if the inhibition of autophagic flux occurs when the process of autophagy is quite completed.
T516 14514-14683 Sentence denotes This hypothesis has been evaluated by Brönnimann, et al. [157], administering by intravenously TAT–Beclin 1 peptide and HCQ (65 mg/kg) in murine models of breast cancer.
T517 14684-14949 Sentence denotes Initially, the first agent induced the autophagic flux with the production of autophagosomes, while in the final phase of the process, the second stopped the autophagy by deacidification of lysosomes, causing the accumulation of autophagic vesicles and tumor death.
T518 14950-15048 Sentence denotes HCQ was administered as HCQ-loaded liposomes, to modulate the onset of autophagy inhibition [158].
T519 15049-15187 Sentence denotes This formulation allows us to overcome the limits of HCQ usage, related to the high doses required, which is often unachievable in humans.
T520 15188-15423 Sentence denotes Relatively high doses of HCQ were loaded in nanoparticles, together with the cytotoxic drug chlorambucil, demonstrating it to be safe and efficient in killing leukemia/lymphoma cancer cells in a human-mouse model of Burkitt’s lymphoma.
T521 15424-15536 Sentence denotes Eight injections of nanoparticles containing 400 mg of HCQ and chlorambucil led to the overall survival of mice.
T522 15537-15623 Sentence denotes These concentrations of free drugs are inapplicable, due to their high toxicity [159].
T523 15624-15917 Sentence denotes As demonstrated by Naso, Wong, Wong, Chen and Hoang [72], HCQ liposomes (60 mg/kg), together with a pH-sensitive targeting peptide that delivered HCQ into the tumor cells and lysosomes, enhanced the chemotherapic effect of conventional anticancer drug doxorubicin in animal models of melanoma.
T524 15918-16141 Sentence denotes Likewise, Vayssade, et al. [160] conceived a nanogel (CA4-FeAlg/HCQ) for co-addressing vascular blocker CA4 and anti-autophagic agent HCQ (30 mg/kg) in tumor blood vessels, to synergistically treat A549 lung cancer in mice.
T525 16142-16391 Sentence denotes Firstly, the release of CA4 exerted anti-angiogenic effects in the vascular site, then FeAlg/HCQ were released into small nanogels and entered in the tumor, where HCQ inhibited autophagy and iron generated ROS with a synergic antitumor effect [161].
T526 16392-16658 Sentence denotes Similarly, De Jong, et al. [162] evaluated the response of an animal model of pancreatic cancer to HCQ (5 mg/kg) and paclitaxel administration, loaded in liposomes, modified with an acid environmental sensitive peptide that is responsible for site-specific delivery.
T527 16659-16745 Sentence denotes Tumor weight, together with the number of liver metastases, was significantly reduced.
T528 16746-16920 Sentence denotes The administration of HCQ is associated with the inhibition of autophagy and the reduction of IL-6 that is responsible for cross-talking between cancer cells and fibroblasts.
T529 16921-17037 Sentence denotes All these events avoided the formation of stroma fibrosis, allowing paclitaxel to easily reach the tumor site [104].
T530 17038-17112 Sentence denotes The synergism results are essential for HCQ activity in pancreatic cancer.
T531 17113-17197 Sentence denotes In monotherapy, indeed, HCQ (800–1200 mg/day) did not achieve significant autophagy.
T532 17198-17398 Sentence denotes This resulted in negligible therapeutic effects in patients with already-treated metastatic pancreatic cancer, of which only 10% were without the progressive disease after two months of therapy [163].
T533 17399-17587 Sentence denotes Therefore, the use of modified formulations, such as liposomes, nanogels, etc., may be a precious tools for drug codelivery at the tumor site, enhancing efficacy and reducing side effects.
T534 17588-17789 Sentence denotes Moreover, the availability of HCQ in those formulations encouraged the use of this molecule in brain tumors, as this formulation highly improved the penetration of this drug in the brain–blood barrier.
T535 17790-17980 Sentence denotes The co-encapsulation of HCQ with a tyrosine kinase inhibitor, ZD6474, exhibited a synergistic effect, increasing the survival of glioma-bearing mice by two-times with respect to free ZD6474.
T536 17981-18150 Sentence denotes Those synergistic effects are attributable to significant inhibition of autophagy exerted by HCQ and might provide a valuable therapeutic tool in glioma treatment [164].
T537 18151-18334 Sentence denotes The anticancer effect of free HCQ at 200–800 mg/day p.o. has been evaluated in two similar clinical trials on glioblastoma patients in concomitant temozolomide drugs and radiotherapy.
T538 18335-18566 Sentence denotes Although a dose-dependent significant increase of autophagy markers, no significant effects on tumor suppression were recorded in both studies, as the dose-limiting toxicity was not allowed to achieve higher doses of HCQ [162,165].
T539 18567-18740 Sentence denotes The maximum tolerated dose is the dose over which at least one patient from six experienced dose-limiting toxicity, including myelosuppression, anorexia, fatigue, or nausea.
T540 18741-18925 Sentence denotes Moreover, it has been proved that HCQ severely altered the organization of the Golgi apparatus and the endolysosomal system in C57BL/6JolaHsd mice under 60 mg/kg/day of HCQ i.p. [166].
T541 18926-19178 Sentence denotes However, different from Rosenfeld’s studies, no maximum tolerated dose was reached for HCQ in combination with chemotherapic temsirolimus, allowing us to perform a dose-escalation study on 27 patients with solid tumors and 12 with a melanoma diagnosis.
T542 19179-19332 Sentence denotes In both cases, the standard intravenous dose of temsirolimus with 1200 mg of oral HCQ was considered safe and tolerated and inhibited tumor growth [167].
T543 19333-19572 Sentence denotes The same authors further assessed the HCQ anticancer properties and dose-limiting toxicity on 40 patients with metastatic melanoma, by administering a dose intense regimen of temozolomide and escalating doses of HCQ (200–1200 mg/day p.o.).
T544 19573-19728 Sentence denotes Patients well tolerated the treatment, showing a positive response in the 14% of cases and stability of disease in 27%, due to the modulation of autophagy.
T545 19729-19817 Sentence denotes No maximum tolerated dose was reached, although common toxicities were manifested [168].
T546 19818-19989 Sentence denotes According to the results of Rangwala, a phase I trial on 25 patients with myeloma demonstrated that the recommended dose of HCQ for a phase II trial is 600 mg twice a day.
T547 19990-20176 Sentence denotes Among eligible patients, 14% experienced a very good response, 14% minor responses, and 45% a period of stability in the disease when the association of HCQ and bortezomib were provided.
T548 20177-20417 Sentence denotes The synergic effect on myeloma was probably due to the combination of inhibition of HCQ on autophagy and bortezomib on proteasomal degradation, leading to the accumulation of misfolded proteins and autophagic vacuoles in cancer cells [169].
T549 20418-20746 Sentence denotes Likewise, doses of 600 mg of HCQ twice a day are not associated with toxicity and its usage as adjuvant therapy with everolimus was well tolerated and produced disease control in 67% of the metastatic clear-cell renal cell carcinoma patients and achieved the rate of six month progression-free survival in 45% of patients [170].
T550 20748-20754 Sentence denotes 2.4.4.
T551 20755-20775 Sentence denotes Bacterial Infections
T552 20776-20906 Sentence denotes HCQ is known to exert an antibacterial effect through the alkalinization of infected organelles, inhibiting bacterial replication.
T553 20907-21072 Sentence denotes In clinical practice, HCQ is not used in monotherapy but in combination with antibiotics, like doxycycline, to improve its bactericidal effects on two main bacteria:
T554 21073-21115 Sentence denotes Coxiella burnetii and Tropheryma whipplei.
T555 21116-21221 Sentence denotes C. burnetii is an obligate intraleukocytic Gram-negative bacterium responsible for query fever (Q fever).
T556 21222-21356 Sentence denotes The infection is mainly caused by direct contact with infected animals, although cases of human transmission have also been described.
T557 21357-21507 Sentence denotes Q fever diagnosis is primally founded on serological examination and based on a different evolution, acute and chronic infection can be distinguished.
T558 21508-21712 Sentence denotes In 50% of cases, the acute phase is asymptomatic, but when the acute phase is symptomatic, it is characterized by a febrile illness, myalgia, headache, chills, atypical hepatitis, and pneumonia [122,123].
T559 21713-21841 Sentence denotes Approximately 2–5% of C. burnetii infections can develop into the chronic phase, leading to endocarditis and vascular infection.
T560 21842-21966 Sentence denotes The risk of developing chronic fever is higher in patients with pre-existing vascular disorders or valvulopathies [123,124].
T561 21967-22058 Sentence denotes C. burnetii is known to replicate in an intracellular phagolysosome with a pH range of 4–5.
T562 22059-22154 Sentence denotes However, at this pH, antibiotics, like doxycycline (DXC), exert only a bacteriostatic activity.
T563 22155-22243 Sentence denotes Therefore, a combination of DXC with a lysosomotropic agent, such as HCQ, was suggested.
T564 22244-22379 Sentence denotes In fact, HCQ was shown to increase the phagolysosomal compartment’s pH by improving the bactericidal activity of doxycycline [125,126].
T565 22380-22508 Sentence denotes The first successful results concerning the treatment of Q fever endocarditis combined with DXC and HCQ date back to 1993 [127].
T566 22509-22721 Sentence denotes These results were later confirmed by a case report of a young infected girl, where the treatment with 200 mg/day of DXC and 600 mg/day of HCQ led to a reduction in serum C. burnetii antibodies within 48 h [128].
T567 22722-23024 Sentence denotes Furthermore, in a 1999 clinical study, the administration of 100 mg DXC twice daily plus 200 mg HCQ three times daily for at least 18 months led to a short duration of therapy and a reduction in recurrences compared to alternative treatments including DXC plus 200 mg ofloxacin three times daily [129].
T568 23025-23253 Sentence denotes Since this moment, all infected subjects have been treated with DXC plus HCQ, as demonstrated by several case reports where this regimen results in an improvement of C. burnetii-related disease [130,131,132,133,134,135,139,140].
T569 23254-23544 Sentence denotes Furthermore, in patients with valvulopathy and diagnosticated acute Q fever (serologic criteria of a phase II IgG titer ≥ 200 and a phase II IgM titer ≥ 50) the administration as prophylaxis of DCX plus HCQ for at least 12 months resulted to be efficient in preventing Q fever endocarditis.
T570 23545-23636 Sentence denotes Contrarily, shorter regimes are associated with a failure of antibiotics prophylaxis [141].
T571 23637-23823 Sentence denotes When Q fever endocarditis occurs, the optimal treatment duration with DXC and HCQ seems to be 18 months for native valve patients and 24 months for subjects with prosthetic valves [142].
T572 23824-23910 Sentence denotes This duration should only be extended in the absence of favorable serological results.
T573 23911-24123 Sentence denotes However, long-term treatment with DXC and HCQ is not without important complications, since both can cause photosensitivity [144], abnormal weight gain [145], severe erythroderma, and impaired visual field [142].
T574 24124-24391 Sentence denotes Besides, it can be said that while the acute phase of the infection can be treated with only 200 mg/day DXC, the chronic phase is more difficult to treat and therapy with 100 mg DXC twice daily with 200 mg HCQ three times daily for 18–24 months was recommended [146].
T575 24392-24480 Sentence denotes Serological titers are used to follow the disease and determine the duration of therapy.
T576 24481-24575 Sentence denotes On the other hand, T. whipplei is a Gram-positive bacterium responsible for Whipple’s disease.
T577 24576-24730 Sentence denotes The natural niche of T. whipplei is the human intestine since, in the intestinal mucosa, the bacterium is taken by macrophages, where it replicates [147].
T578 24731-24893 Sentence denotes This bacterial infection is primally characterized by digestive tract disorders such as diarrhea (75% of cases), malabsorption, and weight loss (80–90% of cases).
T579 24894-25005 Sentence denotes Joint disease may appear more than six years before the diagnosis and occur in more than 80% of patients [148].
T580 25006-25111 Sentence denotes Furthermore, neurological and cardiac disorders can also be frequently associated with Whipple’s disease.
T581 25112-25272 Sentence denotes For years the standard treatment for T. whipplei has included a combination of trimethoprim and sulfamethoxazole; however, relapses were not uncommon [149,150].
T582 25273-25482 Sentence denotes Later, in vitro studies, demonstrated that trimethoprim was inactive on this bacterium [154], while sulfamethoxazole induced bacterial resistance, making the co-administration completely ineffective [154,156].
T583 25483-25646 Sentence denotes Based on the good results of treating C. burnetii infections, it was decided to test in vitro the association DCX/HCQ on T. whipplei, obtaining good results [154].
T584 25647-25736 Sentence denotes DCX/HCQ efficacy on T. whipplei diseases was demonstrated in a clinical trial dated 2014.
T585 25737-25954 Sentence denotes This study showed that the administration of 200 mg/day DCX and 600 mg/day HCQ to 13 patients results in better outcomes (0/13 failures) even after 1 year of treatment, compared to standard antibiotics regimens [155].
T586 25955-26204 Sentence denotes To date, several case reports available in the literature supported a therapy consisting of a combination of HCQ (600 mg/day) and DCX (200 mg/day) for a lifetime or at least one year, followed by a maintenance dosage of DXC used alone [156,157,158].
T587 26205-26376 Sentence denotes In some cases, prophylaxis of intravenous ceftriaxone (2g/day) for the first two weeks followed by HCQ/DXC for at least 12–18 months has been recommended [72,159,160,161].
T588 26377-26653 Sentence denotes Although HCQ was revealed to be effective against bacterial infections, in the last few years, in light of the current epidemiological situation, the research attention has shifted toward HCQ application as an antiviral agent, as it could be seen in the bubble map (Figure 8).
T589 26654-26755 Sentence denotes This visual map is obtained by VOSviewer software, analyzing recurring items from all keywords [171].