Women are increasingly surviving breast cancer, but up to 90% experience unexpected long‐term sequelae as a result of treatment. Symptoms may include physical, functional, emotional, and psychosocial changes that can dramatically alter the quality of life for breast cancer survivors. Primary care clinicians, including midwives, are likely to care for these women and should be familiar with common symptoms, treatment, and best practices to avoid permanent dysfunction. A holistic approach to assessment, treatment, and referral as needed is the most effective strategy. Although women experience significant changes after breast cancer treatment, many fail to receive thorough assessment of their symptoms, education about interventions, and treatment options to optimize health promoting strategies. Disparities exist in treatment availability, options, and survivorship. Long‐term physical changes include anatomic changes, chronic pain, phantom breast pain, axillary web syndrome, and lymphedema. In addition, women may have decreased strength, aerobic capacity, mobility, fatigue, and cognitive dysfunction. Emotional and psychosocial changes include depression, anxiety, fatigue, concerns about body image, and issues with sexuality. Treatment should be multifactorial based on thorough assessment of symptoms and can include medication, exercise, counseling, physical and occupational therapy, and alternative and complementary therapies. Primary care and gynecologic clinicians are well positioned to provide thorough evaluation, education, treatment, and referral for the most common sequelae of mastectomy and breast cancer treatments.
Spermatogonial stem cells (SSCs) maintain spermatogenesis throughout adulthood through balanced self-renewal and differentiation, yet the regulatory logic of these fate decisions is poorly understood. The transcription factors Sal-like 4 (SALL4) and promyelocytic leukemia zinc finger (PLZF; also known as ZBTB16) are known to be required for normal SSC function, but their targets are largely unknown. ChIP-seq in mouse THY1+ spermatogonia identified 4176 PLZF-bound and 2696 SALL4-bound genes, including 1149 and 515 that were unique to each factor, respectively, and 1295 that were bound by both factors. PLZF and SALL4 preferentially bound gene promoters and introns, respectively. Motif analyses identified putative PLZF and SALL4 binding sequences, but rarely both at shared sites, indicating significant non-autonomous binding in any given cell. Indeed, the majority of PLZF/SALL4 shared sites contained only PLZF motifs. SALL4 also bound gene introns at sites containing motifs for the differentiation factor DMRT1. Moreover, mRNA levels for both unique and shared target genes involved in both SSC self-renewal and differentiation were suppressed following SALL4 or PLZF knockdown. Together, these data reveal the full profile of PLZF and SALL4 regulatory targets in undifferentiated spermatogonia, including SSCs, which will help elucidate mechanisms controlling the earliest cell fate decisions in spermatogenesis.
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