His main offence consists of his clones which will keep him safe as he cowardly hides. Belial will use a powerful Comet spell, and continue to confuse you by summoning new copies.
You will need fast killing speed or you will be overwhelmed by his minions. Location Act 5: Bremmtown portal on a path on the right edge of Fauztinville Lore 17, years after the the Fauz-Tin Clan's extermination brought mankind closer to demonkind, humanity bled into nothingness like a flickering candle held against oblivion.
Where the proud Fauztinville once stood now lies Bremmtown, the last colony during the fading of civilization. Inarius, eons prior, attuned the Worldstone to endlessly wane the nephalem's might with each generation, giving rise across time to humanity. In this reality, a Blood Mages Clan of Bartuc's lineage was able to avert the Worldstone's corruption and consequent destruction, unknowingly sealing men's nature to the relentless chains forged by the rogue angel.
Several millennia later, armed with scraps of knowledge, the fragile descendants of those once known as Necromancers felt to haven't yet outlived their usefulness They attempted to save their kin and reunite with the departed by fracturing the veil severing the Spirit Realm from the mortal plane, but were no longer able to deter the dark forces lurking beyond.
Sanctuary turned into a womb of enmity and decay and, as with the creation of the ancient guardian Trag'Oul, champion of Balance, a new guardian for the new world was conceived, the Dark Star Dragon, champion of Blight. Strategy Sensing your lifeforce the Howling Spirits materialize directly upon you enveloping the hero with the freezing coldness of death.
You have no choice but to take some hits, avoid and defense become of vital importance. The shadowy Dark Star Dragon summons additional Howling Spirits and cast a death beam that will make short work of you unless you seek cover as the beams pass by. Bonus Quest Defeat the Dark Star Dragon within 1 minute and 30 seconds after entering the level and without dying.
If you succeed, a single use cube recipe is available to upgrade its drop. You only have 30 seconds after killing the Dark Star Dragon to use the recipe. To apply the trophy for a small bonus, kill the the Dark Star Dragon within 30 seconds of entering the quest and cube the trophy with the charm.
Lore The Sanctum was created at the behest of the Trade Consortium Council of Caldeum, seeking to unite the Mage Clans and make Kehjistan's new capital a beacon of civilization. The academy came to be filled with treasure troves of arcana, becoming a place of learning and growth, and was lead by the famous Archmage Valthek. Recently, defiance has pervaded the academy: numerous students have left due to dissent from the methods and forbidden arts promulgated by the Archmage.
Like with the High Council of Zakarum, Mephisto's malevolence steadily enslaved the mind of Valthek, turning the mightiest mage of Sanctuary into a minister of hatred. Two of his most gifted disciples, noticing the subtle changes in their master, informed the Council and were tasked by the mercantile rulers to craft a set, that once donned, would have allowed the wearer to endure a confrontation against the Archmage.
But, Valthek struck first. He cast away the set pieces and distorted the Yshari Sanctum into a hellish maze. Strategy Each sector of the colossal maze will be inhabited by one of the Archmage's most loyal scholars which will be guarding 2 set pieces: One of the Brotherhood of the Vizjerei and one of the Horadrim. You need these full sets in order to be able to fight Valthek. While wearing the two sets simultaneously, you will acquire new powerful skills which are required to defeat the Archmage.
You must act before the whole of Caldeum is overrun with evil. Lore In the aftermath of the civil war in the Burning Hells, when Belial was exiled, the loyal servant Xazax founded himself stranded on Sanctuary vainly aiming to discover his master location. When his search brought him in the Aranorch wastelands, he perceived the presence of the Lord of Terror within the Dark Wanderer advancing towards Lut Gholein.
Dishearten and horrified he fell into despair, believing Diablo to be on the hunt for him to exact revenge for Belial's transgressions. Paranoid with fear, he called upon his demonic cohorts to provide protection and fled to the Island of Skartara. Find Xazax and put an end to this dark summoning, lest in his madness he turns his followers against the Skovos Isles. Strategy Xazax is attempting to open a portal to Hell and invade Sanctuary with his minions, so the faster you can bring him down the better as you will have to deal with less of his hellish hordes which are invulnerable to mortals.
This will not be easy however for you will be bombarded by Hellfire and choked in corrosive venom if you do not react quickly. Beware his Glacial Nova attack which can slow you down and make you more vulnerable to his Pentients. Lore Lord Aldric Jitan has been crushed, but in his final breath he uttered the incantation to conclude the summoning ritual: Astrogha, the paragon of deceit, has come. The mischievous demon has found shelter in the dark recesses beneath the earth, festering the uderground with his webs and cocoons and bursting forth like a fetid tide his crawling servants.
The demonic spider is already conniving for the sake of Diablo's reign of terror. Venture in the crooked halls of the underground cave and do not let his dreadful visage deters your resolve, he must be struck down. Be cautious Astrogha is never alone. Strategy Astrogha does not usually fight his foes directly, but he does not need to. His summoned Spider Statues serve as gateways for his personal swarm, belching waves of crawling Darklings from the depths of the Black Abyss.
Deal with them quickly, but do not touch the statues! They are protected by one of Astrogha's devious tricks: when destroyed, they will both rejuvenate Astrogha and unleash a curse that cripples the assailant. If left alone, they will eventually collapse on their own. Astrogha also possesses a very powerful but close-ranged Frozen Orb attack and warding spells that teleport him away when damaged.
The golden city protection was entrusted not only to the fortified high-walls or the sorcerers within, but also to the impervious Mount Nymyr embracing Ureh from the North.
It was there where the mage Atanna was positioned during the siege, tasked by her father to guide the scouts of Diablo's legion across a hidden path to the unguarded northern walls. But her too fell victim to the unexpected events of that day.
Despite being on Nymyr's pass, she was reached and entangled by the unruly spell's light and violently traversed the Limbo dimension. Atanna was cast in the deepest plane of the esoteric realm, stranded in an endless black mire where the dimensional planes themselves are born: the obscure World Nexus.
To climb unhindered between the planes to join her father in Ureh, she entered in an inmost sleep state in which she manifested figments of her psyche in the form of lost travelers, probing possible pathways, and as ethereal projections of herself guarding her slumber. Each trophy adds an unique bonus, but only one trophy can be applied, only once, so choose carefully. They consider the Mortal Realm merely an illusion concealing the Spirit World, true plane of reality. It is from there that the Umbaru draw their powers, and it is there where Giyua, guardian of the realm, reside as one of the gods.
Its nature is not entirely known, but Umbaru priests have concluded that in Mbwiru Eikura dwell numerous wrathful spirits. Umbaru's mythology establishes that every living being shares a 'filament', connecting them to the Unformed Land and transcending the mortal illusion. Is it then possible for these bridges to have been tainted by the spreading malice of Diablo and his brethren, granting them a pathway to Mbwiru Eikura?
Strategy Spirit of Giyua will pounce on you as soon as he sees you. This triggers off a devastating six-directional projectile spell which is countered by staying in his melee range. He may also invoke a devastating fiery explosion which has a slow charge up time, be sure to move out of the blast centre. His last ability is to spawn nests.
These summon untargetable, high physical and fire damage dealing minions whose job is to get you on the run, hence making you susceptible to the above spells Cube it with your Umbaru Treasure for an added bonus. Lore Once again a Riftwalker has bridged the inscrutable distances between the Mortal Plane and its esoteric dimension, anchoring its presence to Sanctuary.
The arcane beacon that guided the dreadful invader was none other than that of Belial, the Lord of Lies. The Lesser Evil, exiled from the Burning Hells, now dwelled with his wicked servants in a cave beneath Harrogath, in the recesses of which a portal has opened. It leads to a gaping furnace where occult energies and boundless malice mingle to strengthen the Ascendant Riftwalker cruel determination. Lore The Void, a bleak realm where sorrow beckons the virtuous.
This barren place of torment is bathed by a nefarious essence that nurtures the dark emptiness which serves as a blank canvas on which the soul casts a foul shadow, extending far beyond one's own understanding Every impurity clinging to a visitor's spirit will take form, and in this struggle he shall face wicked beings whose existence is entwined with his own.
Two powerful presences are resonating in this realm: Inarius' and Lilith's. The former has reached for the black void to regain mastery over his might while unhindered by the confines of Hell, the latter instead was banished here by Inarius himself in the forgotten past. Regretfully you will have to face them both, as an obstacle between their eternal damnation and their wicked ambitions.
Be aware that in this cursed journey you will have to overcome your own manifested darkness. Strategy After the clash with Inarius' manifestation, his released malevolence has exposed a pathway leading unmistakably to the Void itself.
Your 7 deadly sins will stand before you, each expressing its own nature. Once you have managed to beat them all, cube their remnants to purify them and craft the Ring of Virtue.
Reach deeper in the fabric of this dimension and use the "Scream of Trag'Oul" to shatter the Ancestral Seal in the last plane of the Void and prepare for the final battle. Bosses The rebellius progenitors of humanity, Inarius and Lilith, will manifest in your presence. Unburdened by the chains of Hell, Inarius is now clad in arcane dark magic boosting an immunity to all damages.
The only way to temporarily break his defense is to kite him into Lilith's wicked Blood Ritual, allowing for a brief critical opening. Inarius casts powerful ice orbs which are a great threat to Lilith. When left untreated the orbs will explode into a massive spikestorm - you must prevent this by hitting them before they do. Brimming with power, both legendary entities will recklessly attack, you'll have to be strategic and turn the tide of battle in your favor.
The primordial structure, where angels harmonize their essences with its resonance to give birth to other seraphims, is now twisting and coiling while gushing out a profane symphony of terror.
Diablo's essence, enhanced by the corrupted Arch, is now echoing in Sanctuary as in Heaven and Hell, resonating with every soul that was once blemished by his terror. The dreadful memories, engraved in the attuned spirits, are being unraveled to the vile Arch and molded to be reborn in the image of wicked past entities.
Ancient memories, such as those recorded in the Tomes of Kalan, are inscribed in the arcane forces permeating Sanctuary and are now seeds for Diablo's despicable creations. The Crystal Arch, on the brink of collapse, strains to repel the impetuous thriving of the parasitic corruption. Its fragile balance cannot hold for long. Strategy As the legendary Edyrems did during the Sin War, you have to stride on their path and protect humanity.
Emmpowered old foes are the roaming forged memories you'll have to face on your path to the final stage. Once on the final stage you'll be confronted by Uldyssian himself. He casts a small wave of four magicbolts in your direction and huge intersecting Deathstrike stripes originating from his position which is the intersecting point and extending outward.
He also summons powerful but slow moving Edyrems that attack only when they're in melee range and seldom cast sacred armor on themselves. It is best to keep moving around the arena as much as possible avoiding his Blink spell. Lore There are many religions in Sanctuary. It has been active both as a single agent , and in combination with alemtuzumab and bortezomib.
Both cladribine and fludarabine have shown efficacy in PTCL, and clofarabine and nelarabine are currently in several clinical trials in T-cell lymphoma. The metabolic enzyme inhibitors, which include deoxycoformycin pentostatin and forodesine, do not incorporate into DNA, unlike the other nucleoside analogs. Pentostatin inhibits adenosine deaminase, increasing the deoxyadenosine triphosphate pool, and forodesine inhibits phosphorylase, increasing the deoxyguanosine triphosphate pool.
Both agents have shown some efficacy in CTCL. Bortezomib, a proteasome inhibitor, has been well tolerated and active as a single agent in relapsed or refractory CTCL patients. Bortezomib has been used in combination with gemcitabine plus doxorubicin, , and recent evidence shows that bortezomib may synergize with pralatrexate in T-cell lymphoma see antifolates section above. Enzastaurin is a selective inhibitor of protein kinase C, which acts in part through the AKT pathway.
Patients in this trial were concurrently treated with radiotherapy and chemotherapy consisting of carboplatin, etoposide, ifosfamide, and dexamethasone. The responses were complete remission CR in 15, partial remission in 14, and early death because of infection in 4. For patients with ATL, results with conventional chemotherapy regimens have been uniformly poor. The authors claimed that patients with acute, chronic, and smoldering ATL significantly benefited from first-line antiviral therapy, whereas patients with ATL lymphoma experienced a better outcome with chemotherapy.
However, considering the potential selection bias in this retrospective study, future prospective studies are needed. There were no dose-limiting toxicities, and no anti—KW antibodies were detected.
Several retrospective studies suggest that there are populations of patients with PTCL that will benefit from transplantation. Disease status at transplantation is a major predictor of success, particularly for autologous transplantation. A prospective study from Germany using chemotherapy and up-front autologous transplantation for PTCL has been reported.
The treatment regimen consisted of 4 to 6 cycles of CHOP, followed by mobilizing therapy with either dexaBEAM dexamethasone, carmustine, melphalan, etoposide, and cytarabine or ESHAP etoposide, methylprednisolone, cytarabine, and cisplatin. Patients in complete or partial remission then underwent myeloablative chemoradiotherapy and ASCT. Patients who did not experience a response to chemotherapy and therefore did not undergo ASCT had a very poor outcome, with a median survival of less than 2 years.
There are currently no randomized studies comparing outcomes between autologous and allogeneic transplantation in the United States.
The Nordic and German lymphoma groups are launching a large, prospective randomized trial to compare the different strategies as consolidation after first-line therapy. In a retrospective single-institution study that compared autologous and allogeneic transplantation, outcomes for autologous transplantation were best when conducted in first remission, and allogeneic transplantation was better for patients with resistant or relapsed disease.
Because of the inferior outcomes with CHOP-based regimens, novel strategies are needed for patients with aggressive T-cell lymphomas. The National Cancer Consortium Network has established evidence-based treatment approaches for T-cell lymphoma and stratifies patients based on stage.
For early-stage patients with localized disease, chemotherapy should be followed by involved field radiotherapy. Selection of first-line therapy based on histopathologic features has not yet been widely used but should be considered. For extranodal subtypes, regimens may be individualized. Likewise, hepatosplenic and intestinal T-cell lymphomas have a poor outcome. In one study, 26 enteropathy-associated T-cell lymphoma patients were treated with CHOP and then methotrexate alternating with ifosfamide, etoposide, and epirubicin.
Therefore, consolidation with allogeneic stem cell transplantation should be considered in patients who have appropriate donors. In conclusion, from this summary of the current state of classification, prognosis, and therapeutic approaches in PTCL, it is apparent that much progress has been made. Although the problem with PTCL treatment in the past was a lack of available therapies, the development of novel therapies necessitates the development of paradigms to combine these agents to improve response rates and durability of responses.
An international registry is currently open and registering patients with newly diagnosed PTCL. In addition, an international tissue bank has been initiated to capture sufficient quantities of clinically annotated and well-characterized specimens. Contribution: F. Conflict-of-interest disclosure: F. The remaining authors declare no competing financial interests.
Correspondence: Francine M. Sign In or Create an Account. Sign In. Skip Nav Destination Content Menu. Close Abstract. Incidence of T-cell lymphomas. Viral associations with T-cell lymphomas. Prognostic features of T-cell lymphomas. Gene expression, cytogenetic and comparative genomic hybridization data. Therapeutic approaches. Evidence-based treatment approaches for PTCL.
Article Navigation. Lymphoid Neoplasia June 23, Peripheral T-cell lymphoma Francine M. Foss , Francine M. This Site. Google Scholar. Julie M. Vose , Julie M. Randy D. Gascoyne , Randy D. Steven T. Rosen , Steven T. BsAbs may become a new focus of future medical and biological research and development. JM prepared the figures and tables.
All authors contributed to the article and approved the submitted version. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
National Center for Biotechnology Information , U. Front Immunol. Published online May 5. Author information Article notes Copyright and License information Disclaimer. This article was submitted to Cancer Immunity and Immunotherapy, a section of the journal Frontiers in Immunology. Received Nov 6; Accepted Apr The use, distribution or reproduction in other forums is permitted, provided the original author s and the copyright owner s are credited and that the original publication in this journal is cited, in accordance with accepted academic practice.
No use, distribution or reproduction is permitted which does not comply with these terms. This article has been cited by other articles in PMC. Abstract Bispecific antibodies BsAbs are antibodies with two binding sites directed at two different antigens or two different epitopes on the same antigen. Keywords: BsAbs, development, platform, mechanism, application. Introduction Various factors and multiple signaling pathways are involved in cancers and other complex diseases.
BsAb Molecular Platforms The main challenge encountered in the development of BsAbs is that there are two types of chains, heavy and light, that when mismatched may produce a variety of side products 9 — Knobs-Into-Holes The knobs-into-holes model is a novel and effective design for engineering antibody heavy chain homodimers for heterodimerization. DAF This platform uses phage display technology to optimize the herceptin antibody with changes to 11 residues in VL CDRs to specifically bind to VEGF while retaining the ability to bind to HER2, thus achieving the binding on a single antibody can simultaneously to two targets TandAbs The TandAbs platform is a tetravalent antibody molecule with two binding sites for each of two antigens Bi-Nanobody The bi-Nanobody platform connects the VH regions of two or more antibody molecules to achieve multi-specific binding.
Open in a separate window. Figure 1. Classical molecular platform of BsAbs and representative antibodies. Mechanisms of Action of BsAbs Because BsAbs have two binding sites directed at different antigens or recognize two different epitopes of one antigen simultaneously, the functioning pathways are quite flexible. Blocking of Inflammatory Factors RA is a chronic inflammatory autoimmune disease of the joints.
Blocking of Dual Signaling Pathways BsAbs can target two specific antigens or different areas of the same antigen at the same time Table 1 Summary of clinical BsAbs and their mechanisms of action. Applications of BsAbs BsAbs are widely used in both diagnosis and therapy. Applications in Diagnostics Clinical Diagnosis Because BsAbs can bind to specific antigens and specific detection sites simultaneously, their design is flexible, sensitive, and convenient.
Figure 2. Some classic structures of BsAbs with CD3 as one of their targets. Pneumonia and Eye Diseases The abuse of antibiotics, has led to an increase in bacterial resistance, and Pseudomonas aeruginosa has emerged as the main culprit behind clinical lung infections Figure 3.
Conclusions Progress in the field of antibody or protein engineering and recombinant DNA technology have led to the establishment of different platforms to generate BsAbs. Acknowledgments We thank miss Mengzu Wang for language editing. References 1. Cancer Treat Rev 41 10 — Schmid AS, Neri D. Advances in Antibody Engineering for Rheumatic Diseases. Nat Rev Rheumatol 15 4 — Science —1. Nisonoff A, Rivers MM. Arch Biochem Biophys 93 —2.
Nature —7. Milstein C, Cuello AC. Hybrid Hybridomas and Their Use in Immunohistochemistry. Nature — Nat Biotechnol 16 7 — Design and Production of Bispecific Antibodies. Antibodies Basel 8 3 Brinkmann U, Kontermann RE. The Making of Bispecific Antibodies.
MAbs 9 2 — Antibodies Basel 7 3 Kontermann RE, Brinkmann U. Bispecific Antibodies. Drug Discov Today 20 7 — Bispecific Antibodies and Their Applications. J Hematol Oncol 8 MAbs 7 1 — Protein Eng 9 7 — Protein Eng Des Sel 23 4 — J Biol Chem 35 — Nat Biotechnol 32 2 —8.
Igawa T. Yakugaku Zasshi 7 —6. Science —4. Gong S, Wu C. Methods — Eigenbrot C, Fuh G. Curr Opin Chem Biol 17 3 —5. MAbs 6 3 —7. MAbs 11 8 — Protein Expr Purif Biochim Biophys Acta Proteins Proteom 1 Protein Eng Des Sel 24 5 — Rose S. Cancer Discov 9 12 Clin Pharmacokinet 59 7 — Sci Transl Med 9 :eaal Blood Supplement 1 Cancer Chemother Pharmacol 82 3 — Cancer Res 76 14 suppl. Am [ CrossRef ] [ Google Scholar ]. Science —7. MAbs 12 1 Immunology 97 4 —8. Nat Protoc 9 10 — MAbs 9 1 — Cancer Res 76 13 — EBioMedicine 52 Nat Biotechnol 25 11 —7.
Methods Mol Biol — Miossec P, Kolls JK. Nat Rev Drug Discov 11 10 — Invest New Drugs 37 5 — Cancer Res 80 16 Supplement Cancer Cell 20 4 — Cancer 24 — J Exp Med 5 — J Biol Chem 4 — MAbs 8 6 — Protein Eng Des Sel 31 — Clin Cancer Res 19 24 — Clin Cancer Res 22 17 — Mol Cancer Ther 15 5 — Protein Eng Des Sel 30 9 — Bispecific T-cell Engagers for Cancer Immunotherapy.
Immunol Cell Biol 93 3 —6. You can craft jewels as well, for an even higher degree of customizing your items. The crafted jewel comes with a few random rare modifiers and always gets all preset modifiers chosen on the Catalyst of Jewelcrafting , which you can acquire by defeating Izual on the Nightmare difficulty.
The preset modifiers may stack with the rare modifiers, creating some very powerful jewels. Multiple bosses have a few percent chance to drop a Trophy Fragment when killed on Hell difficulty. An exception being the Bremmtown trophy, where you must apply the trophy by killing the Dark Star Dragon in under 30 seconds from entering the area. You can upgrade gems to the higher quality levels.
Note that unlike classic Diablo II, this recipe only requires two gems, not three. After creating the Gem Cluster, you can right click it to collect all the gems of the same type in it. You can get a gem out by cubing the Gem Cluster in the Horadric Cube. You can upgrade runes to the next higher rune. This is useful when you need a certain exact rune to create a runeword. After creating the Rune Cluster, you can right click it to collect all the runes of the same type in it.
You can get a rune out by cubing the Rune Cluster in the Horadric Cube. These recipes separate the socket fillers gems, jewels, runes from an item and return both the item and the socket fillers. If you went wild with reanimate items and now you can't see the forest for the reanimated Ents, this recipe can help.
It adds the 'R. This should help out players with slower computers. Do not forget the Arcane Crystal or you will destroy more than you bargained for. You need to stand in the Rogue Encampment in Hell difficulty to use this recipe. Be careful, the cows have been beefed up compared to the regular Diablo II.
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