Replication stress impairs chromosome segregation and preimplantation development in human embryos.

Human cleavage-stage embryos frequently acquire chromosomal aneuploidies during mitosis due to unknown mechanisms. Here, we show that S phase at the 1-cell stage shows replication fork stalling, low fork speed, and DNA synthesis extending into G2 phase. DNA damage foci consistent with collapsed replication forks, DSBs, and incomplete replication form in G2 in an ATR- and MRE11-dependent manner, followed by spontaneous chromosome breakage and segmental aneuploidies. Entry into mitosis with incomplete replication results in chromosome breakage, whole and segmental chromosome errors, micronucleation, chromosome fragmentation, and poor embryo quality. Sites of spontaneous chromosome breakage are concordant with sites of DNA synthesis in G2 phase, locating to gene-poor regions with long neural genes, which are transcriptionally silent at this stage of development. Thus, DNA replication stress in mammalian preimplantation embryos predisposes gene-poor regions to fragility, and in particular in the human embryo, to the formation of aneuploidies, impairing developmental potential.

Heritable human genome editing: Research progress, ethical considerations, and hurdles to clinical practice.

Our genome at conception determines much of our health as an adult. Most human diseases have a heritable component and thus may be preventable through heritable genome editing. Preventing disease from the beginning of life before irreversible damage has occurred is an admirable goal, but the path to fruition remains unclear. Here, we review the significant scientific contributions to the field of human heritable genome editing, the unique ethical challenges that cannot be overlooked, and the hurdles that must be overcome prior to translating these technologies into clinical practice.

Transvaginal sonography in the diagnosis of deep infiltrating endometriosis: A review.

This review summarizes the current evidence regarding the diagnostic accuracy of sonography (US) in women with deep infiltrating endometriosis (DIE). It is well known that transvaginal ultrasound (TVUS) can detect ovarian endometriomas with a high degree of sensitivity. In recent years, US has also been used to detect DIE. In the hands of an experienced sonologist, the sensitivity and specificity of TVUS in the detection of DIE is comparable to those of MRI. TVUS can eliminate the need for an MRI in the majority of patients and reduce the need for diagnostic laparoscopy, proving to be an important tool in preoperative planning. © 2016 Wiley Periodicals, Inc. J Clin Ultrasound 45:313-318, 2017.

Novel therapeutic options for treatment of recurrent implantation failure.

Despite the challenges in studying recurrent implantation failure, progress is currently being made in therapeutic options to help those who suffer from recurrent implantation failure. Three of the most promising therapeutic options for recurrent implantation failure include immune therapies such as peripheral blood mononuclear cells, platelet rich plasma and subcutaneous granulocyte-colony stimulating factor.

Employee benefit or occupational hazard? How employer coverage of egg freezing impacts reproductive decisions of graduate students.

OBJECTIVE: To better understand if employer-based financial coverage of non-medical oocyte cryopreservation impacts the way women make decisions about their reproduction, including the decision to pursue oocyte cryopreservation and the time frame in which they plan to begin family building. DESIGN: Prospective survey study. SETTING: Academic medical center. PATIENTS: Female graduate students at five different institutions in the Boston area. INTERVENTIONS: A 27-question electronic survey. MAIN OUTCOME MEASURES: Likelihood of pursuing oocyte cryopreservation and time frame in which intend to build family, based on presence or absence of employer-based financial coverage. RESULTS: The survey was completed by 171 female graduate students: 63% cited professional goals as their primary reason for delaying childbearing, and 54% indicated that oocyte cryopreservation would allow them to focus more on their career for the next several years. For 59% their main concern about egg freezing was the cost; 81% indicated that they would be more likely to consider egg banking if it were covered by their insurance or paid for by their employer. The majority of participants would not change when they would start building their family based on the presence or absence of employer financial coverage for egg freezing. CONCLUSIONS: The primary concern of female graduate students about egg freezing is the cost. More women would consider elective egg freezing if financial coverage was provided by their employer, but the vast majority would ultimately not change their plans for and timing of family building based on this coverage.

Uterine factor in recurrent pregnancy loss.

OBJECTIVE: To review the current understanding of the role the uterus plays in recurrent pregnancy loss. FINDINGS: Congenital and acquired uterine abnormalities are associated with recurrent pregnancy loss in the first and second trimester. Relevant congenital Mullerian tract anomalies include unicornuate, didelphys, bicornuate and septate uteri. Pregnancy loss has also been associated with acquired uterine abnormalities that distort the uterine cavity such as intrauterine adhesions and submucosal myomas. Initial evaluation of women with recurrent pregnancy loss should include a uterine assessment such as a pelvic ultrasound or sonohysterography. Uterine abnormalities such as uterine septum, intrauterine adhesions and submucosal myomas may be managed surgically with operative hysteroscopy. CONCLUSION: Uterine abnormalities, both congenital and acquired, can be responsible for recurrent pregnancy loss.

Stereotactic Body Radiation Therapy (SBRT) Combined With Chemotherapy for Unresected Pancreatic Adenocarcinoma.

OBJECTIVES: The role of radiation therapy in the management of unresectable pancreatic cancer is controversial. One concern about concurrent chemoradiation relates to the timing of chemotherapy. In contrast to conventional radiation therapy, stereotactic body radiation therapy (SBRT) delivers high doses in a shorter duration resulting in minimal disruption in chemotherapy. Here, we report our results of patients treated with SBRT and chemotherapy for inoperable pancreatic cancer. MATERIALS AND METHODS: Thirty-eight patients treated with SBRT and chemotherapy for locally advanced, borderline resectable, and medically inoperable pancreatic cancer at our institution from January 2008 to December 2012 were included in this retrospective analysis. Treatment was delivered in 5 fractions of 5 or 6 Gy per fraction over 5 days. Toxicities were scored using the Common Terminology Criteria for Adverse Events version 3. Survival was calculated using the Kaplan-Meier method. RESULTS: The median age was 70 years (range, 45 to 90 y). Eastern Cooperative Oncology Group performance status ranged from 0 to 3. Thirty-four patients received concurrent chemotherapy. Four patients received sequential chemotherapy. Median overall survival was 14.3 months and median progression-free survival was 9.2 months from diagnosis. From radiation, overall survival and progression-free survival were 12.3 and 6.8 months, respectively. The overall local control rate was 79%. Acute toxicity was minimal. Severe late SBRT-related toxicities included 1 grade 3 gastric outlet obstruction, 1 grade 4 biliary stricture, and 1 grade 5 gastric hemorrhage. CONCLUSIONS: SBRT combined with chemotherapy for unresectable pancreatic cancer is convenient, feasible, and generally well tolerated. Outcomes of SBRT combined with chemotherapy compare favorably to results obtained with chemotherapy and conventional radiation therapy.