Abstract The Janus kinase (JAK) signal transducer and activator of transcription (JAK-STAT) pathway is an evolutionarily conserved mechanism of transmembrane signal transduction that enables cells to communicate with the exterior environment. Various cytokines, interferons, growth factors, and other specific molecules activate JAK-STAT signaling to drive a series of physiological and pathological processes, including proliferation, metabolism, immune response, inflammation, and malignancy. Dysregulated JAK-STAT signaling and related genetic mutations are strongly associated with immune activation and cancer progression. Insights into the structures and functions of the JAK-STAT pathway have led to the development and approval of diverse drugs for the clinical treatment of diseases. Currently, drugs have been developed to mainly target the JAK-STAT pathway and are commonly divided into three subtypes: cytokine or receptor antibodies, JAK inhibitors, and STAT inhibitors. And novel agents also continue to be developed and tested in preclinical and clinical studies. The effectiveness and safety of each kind of drug also warrant further scientific trials before put into being clinical applications. Here, we review the current understanding of the fundamental composition and function of the JAK-STAT signaling pathway. We also discuss advancements in the understanding of JAK-STAT–related pathogenic mechanisms; targeted JAK-STAT therapies for various diseases, especially immune disorders, and cancers; newly developed JAK inhibitors; and current challenges and directions in the field. 

/pdf/evolving-cognition-of-the-jak-stat-signaling-pathway-1waf67de.pdf

Evolving cognition of the JAK-STAT signaling pathway: autoimmune disorders and cancer

PURPOSE Homologous recombination deficiency (HRD) is highly prevalent in triple-negative breast cancer (TNBC) and associated with response to PARP inhibition (PARPi). Here, we studied the prevalence of HRD in non-TNBC to assess the potential for PARPi in a wider group of patients with breast cancer. METHODS HRD status was established using targeted gene panel sequencing (360 genes) and BRCA1 methylation analysis of pretreatment biopsies from 201 patients with primary breast cancer in the phase II PETREMAC trial (ClinicalTrials.gov identifier: NCT02624973). HRD was defined as mutations in BRCA1, BRCA2, BRIP1, BARD1, or PALB2 and/or promoter methylation of BRCA1 (strict definition; HRD-S). In secondary analyses, a wider definition (HRD-W) was used, examining mutations in 20 additional genes. Furthermore, tumor BRCAness (multiplex ligation-dependent probe amplification), PAM50 subtyping, RAD51 nuclear foci to test functional HRD, tumor-infiltrating lymphocyte (TIL), and PD-L1 analyses were performed. RESULTS HRD-S was present in 5% of non-TNBC cases (n = 9 of 169), contrasting 47% of the TNBC tumors (n = 15 of 32). HRD-W was observed in 23% of non-TNBC (n = 39 of 169) and 59% of TNBC cases (n = 19 of 32). Of 58 non-TNBC and 30 TNBC biopsies examined for RAD51 foci, 4 of 4 (100%) non-TNBC and 13 of 14 (93%) TNBC cases classified as HRD-S had RAD51 low scores. In contrast, 4 of 17 (24%) non-TNBC and 15 of 19 (79%) TNBC biopsies classified as HRD-W exhibited RAD51 low scores. Of nine non-TNBC tumors with HRD-S status, only one had a basal-like PAM50 signature. There was a high concordance between HRD-S and either BRCAness, high TIL density, or high PD-L1 expression (each P < .001). CONCLUSION The prevalence of HRD in non-TNBC suggests that therapy targeting HRD should be evaluated in a wider breast cancer patient population. Strict HRD criteria should be implemented to increase diagnostic precision with respect to functional HRD.

Homologous Recombination Deficiency Across Subtypes of Primary Breast Cancer

Key Points Question Are there racial and ethnic disparities in survival among participants enrolled in clinical trials receiving standardized initial care for early-stage breast cancer? Findings In this cohort study with 9479 participants, pooled survival data suggest that survival differences exist even within clinical trial participants receiving similar initial care. Subgroups, defined by tumor subtype, age, and/or body mass index, that may drive racial and ethnic disparities in survival were identified. Meaning These findings suggest potential factors contributing to racial and ethnic disparities in survival of patients with breast cancer; it is critical to evaluate interventions for improvement.

Age, Body Mass Index, Tumor Subtype, and Racial and Ethnic Disparities in Breast Cancer Survival

Genomic Characterization of Aggressive Breast Cancer in Younger Women

Breast cancer is the most common malignancy diagnosed during or directly after pregnancy. Differences in pathogenesis and prognosis identify two distinct patient groups, those with breast cancer during pregnancy and those with postpartum breast cancer which, for reasons not completely understood, is associated with worse outcomes. Compared with breast cancer in the non-pregnant patient, several limitations in terms of both local and systemic therapy are applied to limit fetal harm. Treatment is nevertheless delivered with curative intent, therefore avoiding harmful delays in therapy initiation, unnecessary therapy de-escalation or chemotherapy dose modifications is strongly recommended. In this short commentary, we briefly review current evidence and treatment guidelines and provide recommendations for optimal oncologic management of pregnancy-related breast cancer.

Breast cancer during pregnancy-The oncologist's point of view.

Genomic characterisation of hormone receptor-positive breast cancer arising in very young women.

K-21 Neurological Differential Diagnosis in sheep: The relevance of the neurological examination

/pdf/ileostomy-closure-is-timing-of-the-essence-1phn4jdn.pdf

Ileostomy closure: is timing of the essence?

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Genomic characterisation of hormone receptor-positive breast cancer arising in very young women.

K-21 Neurological Differential Diagnosis in sheep: The relevance of the neurological examination

Ileostomy closure: is timing of the essence?