CCN5/WISP-2 restores ER-∝ in normal and neoplastic breast cells and sensitizes triple negative breast cancer cells to tamoxifen.

CCN5/WISP-2 is an anti-invasive molecule and prevents breast cancer (BC) progression. However, it is not well understood how CCN5 prevents invasive phenotypes of BC cells. CCN5 protein expression is detected in estrogen receptor-α (ER-α) -positive normal breast epithelial cells as well as BC cells, which are weakly invasive and rarely metastasize depending on the functional status of ER-α. A unique molecular relation between CCN5 and ER-α has been established as the components of the same signaling pathway that coordinate some essential signals associated with the proliferation as well as delaying the disease progression from a non-invasive to invasive phenotypes. Given the importance of this connection, we determined the role of CCN5 in regulation of ER-α in different cellular settings and their functional relationship. In a genetically engineered mouse model, induced expression of CCN5 in the mammary ductal epithelial cells by doxycycline promotes ER-α expression. Similarly, CCN5 regulates ER-α expression and activity in normal and neoplastic breast cells, as documented in various in vitro settings such as mouse mammary gland culture, human mammary epithelial cell and different BC cell cultures in the presence or absence of human recombinant CCN5 (hrCCN5) protein. Mechanistically, at least in the BC cells, CCN5 is sufficient to induce ER-α expression at the transcription level via interacting with integrins-α6ß1 and suppressing Akt followed by activation of FOXO3a. Moreover, in vitro and in vivo functional assays indicate that CCN5 treatment promotes response to tamoxifen in triple-negative BC (TNBC) cells possibly via restoring ER-α. Collectively, these studies implicates that the combination treatments of CCN5 (via activation of CCN5 or hrCCN5 treatment) and tamoxifen as potential therapies for TNBC.

CCN5/WISP-2 promotes growth arrest of triple-negative breast cancer cells through accumulation and trafficking of p27(Kip1) via Skp2 and FOXO3a regulation.

The matricellular protein CCN5/WISP-2 represents a promising target in triple-negative breast cancer (TNBC) because treatment or induced activation of CCN5 in TNBC cells promotes cell growth arrest at the G0/G1 phase, reduces cell proliferation and delays tumor growth in the xenograft model. Our studies found that the p27(Kip1) tumor suppressor protein is upregulated and relocalized to the nucleus from cytoplasm by CCN5 in these cells and that these two events (upregulation and relocalization of p27(Kip1)) are critical for CCN5-induced growth inhibition of TNBC cells. In the absence of CCN5, p27(Kip1) resides mostly in the cytoplasm, which is associated with the aggressive nature of cancer cells. Mechanistically, CCN5 inhibits Skp2 expression, which seems to stabilize the p27(Kip1) protein in these cells. On the other hand, CCN5 also recruits FOXO3a to mediate the transcriptional regulation of p27(Kip1). The recruitment of FOXO3a is achieved by the induction of its expression and activity through shifting from cytoplasm to the nucleus. Our data indicate that CCN5 blocks PI3K/AKT signaling to dephosphorylate at S318, S253 and Thr32 in FOXO3a for nuclear relocalization and activation of FOXO3a. Moreover, inhibition of α6ß1 receptors diminishes CCN5 action on p27(Kip1) in TNBC cells. Collectively, these data suggest that CCN5 effectively inhibits TNBC growth through the accumulation and trafficking of p27(Kip1) via Skp2 and FOXO3a regulation, and thus, activation of CCN5 may have the therapeutic potential to kill TNBC.

A quit smoking group. Pilot study.

1. While the rate of smoking is extremely high among persons with mental illness, there have been efforts to assist this population to quit. A 10-week smoking cessation program was provided for 10 highly nicotine dependent persons with persistent mental illness. 2. No significant differences were found in psychiatric symptoms or drug side effects prior to and after smoking cessation efforts. Four months later, for the 7 subjects who completed the program, 14% were abstinent, 43% maintained reduced tobacco intake, and 43% had resumed previous smoking patterns. 3. Specific barriers to quitting include a lack of nonsmoking coping skills, long-term identity as a smoker, ready access to tobacco products, nicotine addiction, and limited nonsmoking social support.

The status of lower-limb amputation in Bangladesh: a 6-year review.

We conducted a review of 450 single lower-limb amputations performed in our hospital in Bangladesh between July 1982 and June 1987. The incidence of amputation in the specific area of 1000000 inhabitants covered by the hospital was 0.75/10(3) per year. The indications for amputation were: limb ischemia in 366 patients (81%), traumatic crush injury in 45 (10%), diabetes-associated complications in 20 (5%), severe limb infection in 10 (2%), and neoplasm growth in 10 (2%). The ratio of above-knee (AK) to below-knee (BK) amputation was 1:65, and 36 patients (8%) required reamputation, 22 of whom had undergone BK amputation previously. Thus, the number of patients with a final amputation at AK level was 302 (67%). The operative mortality was 21% and the uncomplicated primary wound healing rate was 89% within the survivors. Among the 355 patients who survived the amputation, 265 (75%) were given a prosthesis, 50 (14%) refused a prosthesis, and the remaining 40 (11%) were unfit for a prosthesis. Rehabilitation was successful in 44% of the AK and 86% of the BK amputees. In conclusion, when amputation is inevitable, maximum consideration should be given to the type of surgery performed to avoid rehabilitation failure.

Roxatidine versus ranitidine in the treatment of patients with duodenal ulcer: a randomized, double-masked, multicenter study.

The comparative efficacy of roxatidine and ranitidine in the treatment of patients with acute duodenal ulcer was assessed at 4 and 6 weeks in this multicenter study. Ninety-four of 192 patients were given roxatidine in a single nightly dose of 150 mg, and 98 patients were given ranitidine in a single nightly dose of 300 mg. All the patients had endoscopically proven duodenal ulcer. Of the 171 assessable patients, ulcers were healed in 88% of the roxatidine group (73 of 83) and in 84% of the ranitidine group (74 of 88). No serious adverse events were reported in either group. We conclude that roxatidine 150 mg once daily is as effective and safe for the treatment of acute duodenal ulcer as ranitidine 300 mg once daily.

Lymphangiovenous malformation--a rare cause of giant retroperitoneal cyst.

A giant retroperitoneal cyst manifesting as congenital inguino-scrotal swelling to begin with, is reported. The abdominal swelling became clinically obvious at the age of five years because of rapid enlargement over a period of one month. A multiloculated cyst was revealed on preoperative ultrasonography. Intracystic hemorrhage necessitated emergency surgical exploration and excision. Histology of the cyst revealed lymph-angio-venous malformation.

Tuberculosis of the thyroid gland: a clinicopathological profile of four cases and review of the literature.

Four cases of tuberculosis of the thyroid with different presentations including chronic sinus (following drainage of thyroid abscess), thyrotoxicosis, severe dysphagia clinically mimicking malignancy and euthyroid multinodular goitre are described. Except in the case presenting with chronic sinus (discharging acid-fast bacilli), the diagnosis was a pathological surprise (cytopathology in one and histopathology in two). Only in one case was there evidence of disease outside the cervical region. All cases showed multiple coalescing and caseating epitheloid cell granulomas along with giant cells, which are considered as diagnostic of tuberculous thyroiditis even if acid fast bacilli cannot be demonstrated. The literature is reviewed and the pathogenesis discussed.

Wegener's vasculitis: diagnostic and therapeutic problems.

A case of Wegener's granulomatosis (WG) presenting with pulmonary manifestation which were initially suspected to be due to tuberculosis is being reported. Renal involvement appeared later. He developed complications of antitubercular treatment and of immunosuppression. The difficulties in distinguishing pulmonary manifestation of WG from tuberculosis and other diagnostic and therapeutic problems are discussed.

Fine needle aspiration cytology of the spleen in visceral leishmaniasis.

We describe the fine needle aspiration cytologic study of 210 splenic aspirates from patients clinically diagnosed as having visceral leishmaniasis. Of these, 147 aspirates were found to be positive for Leishmania donovani bodies. We highlighted the cytomorphology of these positive smears. A majority of the cases showed an increase in the number and size of reticuloendothelial cells, with altered shapes, variations in the cytoplasm and decreased white pulp elements. In some of these cases (10%), immature erythroid cells were also found.

The dynamics of progression of coronary atherosclerosis studied in 168 medically treated patients who underwent coronary arteriography three times.

To study the dynamics of progression of coronary atherosclerosis we analyzed findings in 168 patients who underwent coronary arteriography three times without undergoing coronary surgery or percutaneous transluminal coronary angioplasty. Of 66 patients who had progression in interval 1 (from first to second coronary arteriogram), 32 also had progression in interval 2 (from second to third coronary arteriogram); of 102 patients who had no progression in interval 1, 37 had progression in interval 2. In only 9 of the 32 patients who had progression during both intervals was the same lesion involved, and in six of these patients other lesions were also involved. Progression correlated with the duration of the interval between catheterizations, an increase in symptoms, and the occurrence of myocardial infarction. Analysis of variance showed no significant differences in mean values for age, blood pressure, total serum cholesterol, and serum triglycerides in the four main progression groups. Progression of coronary atherosclerosis is a highly unpredictable process. It follows a nonlinear course, and information derived from sequential coronary arteriograms is of little value in predicting future progression.