T-Cell Receptor Beta Variable Gene Polymorphism Predicts Immune-Related adverse Events During Checkpoint Blockade Immunotherapy

BACKGROUND: Immune checkpoint inhibitors have revolutionized cancer treatment. However, they are associated with a unique spectrum of side effects, called immune-related adverse events (irAEs), which can cause significant morbidity and quickly progress to severe or life-threatening events if not treated promptly. Identifying predictive biomarkers for irAEs before immunotherapy initiation is therefore a critical area of research. Polymorphisms within the T-cell receptor beta (TCRB) variable (TRBV) gene have been implicated in autoimmune disease and may be mechanistically linked to irAEs. However, the repetitive nature of the TCRB locus and incomplete genome assembly has hampered the evaluation of TRBV polymorphisms in the past. PATIENTS AND METHODS: We used a novel method for long-amplicon next generation sequencing of rearranged TCRB chains from peripheral blood total RNA to evaluate the link between TRBV polymorphisms and irAEs in patients treated with immunotherapy for cancer. We employed multiplex PCR to create amplicons spanning the three beta chain complementarity-determining regions (CDR) regions to enable detection of polymorphism within the germline-encoded framework and CDR1 and CDR2 regions in addition to CDR3 profiling. Resultant amplicons were sequenced via the Ion torrent and TRBV allele profiles constructed for each individual was correlated with irAE annotations to identify haplotypes associated with severe irAEs (≥ grade 3). RESULTS: Our study included 81 patients who had irAEs when treated with immunotherapy for cancer. By using principal component analysis of the 81 TRBV allele profiles followed by k-means clustering, we identified six major TRBV haplotypes. Strikingly, we found that one-third of this cohort possessed a TRBV allele haplotype that appeared to be protective against severe irAEs. CONCLUSION: The data suggest that long-amplicon TCRB repertoire sequencing can potentially identify TRBV haplotype groups that correlate with the risk of severe irAEs. Germline-encoded TRBV polymorphisms may serve as a predictive biomarker of severe irAEs

Situating Arab women’s writing in a feminist ‘global gothic’ : madness, mothers and ghosts

This article sketches a new way of approaching some contemporary Levantine (Egyptian and Lebanese) feminist texts. Extending Glennis Byron’s notion of the ‘global gothic’, I examine Hanan Al-Shaykh’s The Story of Zahra (1986), Mansoura Ez Eldin’s Maryam’s Maze (2007) and Joumana Haddad’s The Seamstress’ Daughter (2019) as examples of an Arab feminist Gothic approach, which serves as a framework to theorise difficult and pressing questions that feminism poses regarding women’s rights. Arab feminist Gothic writers use the jahiliyyah period, or the ‘time of ignorance’, as a folkloric referential backdrop for texts which theorise the female condition under contemporary patriarchal society. The presence of ghosts, madness, doubles in the form of the folkloric qarina spirit-doubles and dreams can be read as part of a local Gothic feminist mode. This as-yet unacknowledged Arab feminist Gothic tradition, while emerging from debates over statehood and postcolonial subjectivities, delves into the intensity of personal traumas through the lens of women’s relationships to other women, especially mothers and daughters. Taking Arab feminist fiction as its focus, this article models how feminist scholarship can use genre, particularly the Gothic, to trace artistic feminist theorising in non-western contexts

Sa'īd al-Shartūnī : a humanist of the Arab Renaissance (nahḍah)

EThOS - Electronic Theses Online ServiceGBUnited Kingdo

"Nahḍa" Epistolography: al-Shartūnī’s "al-Shihāb" and the Western Art of Letter-Writing

Letter-writing represents one of the most important modes of communication in Islamic and Western societies. Arabic manuals on epistolography and collections of model letters abound throughout the medieval period and continued to be written right up to modern times. The research to date, however, has tended to focus on works of the pre-modern periods which rooted in the Islamic tradition cater primarily for a Muslim audience. Little is known about manuals produced in the Arab nahḍa and it is not clear what factors might have influenced them. Moving into the largely uncharted territory of nahḍa letter-writing manuals, this article takes a detailed look at al-Shartūnī’s manual on epistolary theory and model letters, al-Shihāb al-thāqib. An analysis of this work reveals it as a significant attempt by al-Shartūnī to appropriate elements of the Western ars dictaminis (the art of letter-writing) into his manual for the benefit of an Arab-Christian audience in the nahḍa

INTRAVITREAL ANTI-VASCULAR ENDOTHELIAL GROWTH FACTOR INJECTIONS FOR EXUDATIVE RETINAL ARTERIAL MACROANEURYSMS

Purpose: There is no established therapy for exudative-hemorrhagic complications in primary retinal arteriolar macroaneurysm (RAM)

T-cell receptor beta variable gene polymorphism predicts immune-related adverse events during checkpoint blockade immunotherapy

Background Immune checkpoint inhibitors have revolutionized cancer treatment. However, they are associated with a unique spectrum of side effects, called immune-related adverse events (irAEs), which can cause significant morbidity and quickly progress to severe or life-threatening events if not treated promptly. Identifying predictive biomarkers for irAEs before immunotherapy initiation is therefore a critical area of research. Polymorphisms within the T-cell receptor beta (TCRB) variable (TRBV) gene have been implicated in autoimmune disease and may be mechanistically linked to irAEs. However, the repetitive nature of the TCRB locus and incomplete genome assembly has hampered the evaluation of TRBV polymorphisms in the past.Patients and methods We used a novel method for long-amplicon next generation sequencing of rearranged TCRB chains from peripheral blood total RNA to evaluate the link between TRBV polymorphisms and irAEs in patients treated with immunotherapy for cancer. We employed multiplex PCR to create amplicons spanning the three beta chain complementarity-determining regions (CDR) regions to enable detection of polymorphism within the germline-encoded framework and CDR1 and CDR2 regions in addition to CDR3 profiling. Resultant amplicons were sequenced via the Ion Torrent and TRBV allele profiles constructed for each individual was correlated with irAE annotations to identify haplotypes associated with severe irAEs (≥ grade 3).Results Our study included 81 patients who had irAEs when treated with immunotherapy for cancer. By using principal component analysis of the 81 TRBV allele profiles followed by k-means clustering, we identified six major TRBV haplotypes. Strikingly, we found that one-third of this cohort possessed a TRBV allele haplotype that appeared to be protective against severe irAEs.Conclusion The data suggest that long-amplicon TCRB repertoire sequencing can potentially identify TRBV haplotype groups that correlate with the risk of severe irAEs. Germline-encoded TRBV polymorphisms may serve as a predictive biomarker of severe irAEs