Loss of RAB25 Cooperates with Oncogenes in the Transformation of Human Mammary Epithelial Cells (HMECs) to Give Rise to Claudin-Low Tumors.

The loss of RAB25 expression-RAS superfamily of GTPase characteristic of numerous breast cancers-corresponds with H-RAS point mutations, particularly in triple-negative breast cancers (TNBC), a subtype associated with a poor prognosis. To address the poorly understood factors dictating the progression of TNBC tumors, we examine the cooperative effects that loss of RAB25 expression in human mammary epithelial cell (HMEC) lines with H-RAS mutations confers in tumorigenesis. HMECs were immortalized by transduction with LXSN CDK4 R24C, a mutant form of cyclin-dependent kinase, followed by transduction with hTERT, a catalytic subunit of the telomerase enzyme. We found that with the loss of RAB25 and overexpression of mutant H-RAS61L, immortal HMECs transformed toward anchorage-independent growth and acquired an increased ability to migrate. Furthermore, cells express low CD24, high CD44, and low claudin levels, indicating stem-like properties upon transformation. Besides, loss of RAB25 and overexpression of H-RAS61L resulted in increased expression of transcription factors Snail and Slug that drive these cells to lose E-cadherin and undergo epithelial-mesenchymal transition (EMT). This study confirms that loss of RAB25 and overexpression of mutant H-RAS can drive HMECs toward a mesenchymal stem-like state. Our findings reveal that RAB25 functions as a tumor suppressor gene, and loss of RAB25 could serve as a novel biomarker of the claudin-low type of TNBC.

Long working hours and obstetric complications: A cross-sectional study among female doctors.

Objective: To investigate the effects of long working hours on pregnancy complications and obstetric outcomes among female doctors working in tertiary care hospitals of Karachi. Study design: A cross-sectional study was conducted on 149 female MBBS graduates (mean age: 33.5 ± 7.3 years) who had conceived at least once, currently working in two tertiary-care hospitals of Karachi. Data was collected through a self-administered questionnaire containing questions regarding demography and course of 1st pregnancy of the participants including working hours, antenatal and natal complications. Means and standard deviations were calculated for continuous variables with frequencies and percentages for categorical variables. The association between long working hours and different antenatal and natal complications was investigated using Chi-square test and T-test. Results: Out of 149 participants included in final analysis, 85.9 % doctors gave birth to alive babies while 12.8 % had miscarriages and 1.3 % had stillbirth. Mean working hours during the three trimesters were found to be 53.76, 53.66 and 48.7, respectively. 43 % doctors experienced at least one antenatal complication during their pregnancy. Women who worked more than or equal to 55 h per week during 1st, 2nd and 3rd trimester of their pregnancy experienced more antenatal complications than women who worked less than 55 h (p-value=0.042, 0.021 and 0.018 respectively). 61.7 % females experienced at least one natal complication, most common of which was induction of Labour (39.1 %). Natal complications were significantly associated with increased workload during 2nd trimester (mean 58 vs 46 h, p-value 0.040). Doctors belonging to surgical specialty had 2.7 times higher risk of developing at least one natal complication than doctors of medical specialty (95 % Cl: 1.235-5.870). Conclusion: Long working hours during pregnancy are associated with antenatal complications among female doctors. Natal complications were only significantly related to long working hours during 2nd trimester of pregnancy, however, female surgeons are more prone to develop natal complications than doctors belonging to medical specialties.

Systemic Mastocytosis in Association with Small Lymphocytic Lymphoma.

BACKGROUND Systemic mastocytosis with an associated hematologic non-mast cell lineage disease is a rare entity, and the majority of systemic mastocytosis cases are associated with myeloid neoplasm. Lymphoproliferative disorders are less commonly associated with systemic mastocytosis and a few cases of systemic mastocytosis associated with chronic lymphocytic leukemia have been described in the literature. CASE REPORT We present a case of indolent systemic mastocytosis associated with small lymphocytic lymphoma. The bone marrow biopsy demonstrated mast cells in the form of clusters and perivascular distribution on immunohistochemistry for tryptase, CD2, and CD25 markers. In addition, 30% involvement by small lymphocytic lymphoma was discovered in the form of interstitial lymphoid aggregates composed of small lymphocytes. Flow cytometry showed B-cells positively stained for CD19, CD20, CD5, CD23, and kappa light chains, and the CD38 expression was <5%. CONCLUSIONS In systemic mastocytosis with an associated hematologic non-mast cell lineage disease, the combination of systemic mastocytosis associated with small lymphocytic lymphoma is rare and the management strategy follows the principle of treating the two entities individually as if they are not related. Clinical surveillance is indicated for indolent systemic mastocytosis and low-risk small lymphocytic lymphoma to monitor for disease progression.

Non-Seminomatous Germ Cell Tumor Presenting with Superior Vena Cava Syndrome.

BACKGROUND Primary mediastinal non-seminomatous germ cell tumors (NSGCTs) are aggressive and carry a poor five-year disease free survival rate even with aggressive treatment. We describe a young adult male with primary mediastinal NSGCT presenting with airway obstruction and superior vena cava syndrome (SVCS). CASE REPORT The patient presented with four weeks of nonproductive cough, weight loss, and right-sided pleuritic chest pain. Chest computed topography (CT) imaging demonstrated a right-sided mediastinal mass determined as a yolk sac tumor on biopsy. The patient underwent induction chemotherapy with etoposide and cisplatin for stage III NSGCT. In the interim, he developed SVCS warranting a second cycle of chemotherapy along with intravenous steroids, with notable improvement in symptoms. However, serial alpha-fetoprotein (AFP) measurements showed progressively increasing levels up to a maximum of 18,781 ng/mL indicating treatment failure. He is currently on salvage chemotherapy. CONCLUSIONS Obstruction of the SVC by external compression is often a manifestation of a malignant process in the thorax. SVCS is a medical emergency and occurs in 6% of patients with mediastinal GCTs. Historically, irradiation was initiated without a histologic diagnosis to relieve the life-threatening obstruction. However, newer data suggest that it is acceptable to defer therapy until a full diagnostic workup is completed. This case highlights the malignant nature of primary mediastinal NSGCTs. In addition, inasmuch as SVCS is dramatic in presentation, it is important to recognize that symptomatic obstruction often develops over weeks or longer. In a hemodynamically stable patient, an accurate histologic diagnosis prior to starting treatment is essential in guiding therapy.