A new ER-specific photosensitizer unravels (1)O2-driven protein oxidation and inhibition of deubiquitinases as a generic mechanism for cancer PDT.

Photosensitizers (PS) are ideally devoid of any activity in the absence of photoactivation, and rely on molecular oxygen for the formation of singlet oxygen ((1)O2) to produce cellular damage. Off-targets and tumor hypoxia therefore represent obstacles for the use of PS for cancer photodynamic therapy. Herein, we describe the characterization of OR141, a benzophenazine compound identified through a phenotypic screening for its capacity to be strictly activated by light and to kill a large variety of tumor cells under both normoxia and hypoxia. This new class of PS unraveled an unsuspected common mechanism of action for PS that involves the combined inhibition of the mammalian target of rapamycin (mTOR) signaling pathway and proteasomal deubiquitinases (DUBs) USP14 and UCH37. Oxidation of mTOR and other endoplasmic reticulum (ER)-associated proteins drives the early formation of high molecular weight (MW) complexes of multimeric proteins, the concomitant blockade of DUBs preventing their degradation and precipitating cell death. Furthermore, we validated the antitumor effects of OR141 in vivo and documented its highly selective accumulation in the ER, further increasing the ER stress resulting from (1)O2 generation upon light activation.

Menstrual activity of matrix metalloproteinases is decreased in endometrium regenerating after thermal ablation.

BACKGROUND: Menstruation is associated with a striking increase in matrix metalloproteinase (MMP) activity. However, it is still unknown whether the level of MMP activity correlates with the amount of menstrual bleeding. METHODS: We used histochemistry to investigate the degradation of the extracellular matrix (ECM), and immunohistochemical labelling and zymographic analysis to determine the level of expression and activity of MMP-2 and -9, and of their tissue inhibitors (TIMPs) -1, -2 and -3, in endometria sampled during menstruation in 14 women experiencing excessive menstrual bleeding and in 10 women successfully treated for menorrhagia by thermal ablation of the endometrium. RESULTS: After thermal ablation, regenerated menstrual endometria showed reduced areas of collagen fibre lysis and increased content of TIMP-1 and TIMP-2 compared with endometria from non-treated menorrhagic women. Surprisingly, treated endometria contained more latent gelatinase A (proMMP-2) but a lower proportion of the active form of gelatinase B (MMP-9) than non-treated endometria. CONCLUSIONS: These results suggest that ECM degradation is decreased at menstruation in the endometrium regenerated after thermal ablation, mostly because of an increased TIMP expression. This represents the first molecular explanation for the decreased amount of menstrual bleeding.

[Bone metastasis of a prostate tumor and osteosynthesis material. A case report]. / Métastase osseuse d'une tumeur de la prostate et matériel d'ostéosynthèse. A propos d'un cas.

The detection of metastatic deposits at the site of previous osteosynthesis is difficult. Bone imaging and scanning with technectium 99m are unhelpful in differentiating between osteomyelitis, Paget's disease and a bone metastasis. The authors present details of a patient who had undergone osteosynthesis for a fracture of the left tibia in 1983. In October 1989 signs of inflammatory change appeared at the site of the previous fracture. It was initially treated as if it were osteomyelitis, with curettage and insertion of gentamycin beads, although no organisms were grown. Eventually the patient was transferred to the author's hospital and further investigation revealed a carcinoma of the prostate. Histological examination of biopsy specimens from the left tibia confirmed the presence of a metastasis from this growth.

The operative treatment of intraarticular calcaneal fractures. Indications, technique, and results in 257 cases.

Since 1972, 257 intraarticular fractures of the calcaneus have been treated with operative intervention. A lateral incision and a third tubular plate were used in all cases. The functional results were considered excellent or good in 85%, and there was an infection rate of 2.7%. Although 50% of patients showed a reduced mobility of the subtalar joint, pain and limited ambulation were rare. Only six patients required a late subtalar arthrodesis.

Triflusal versus acetylsalicylic acid: a double-blind study for the prophylaxis of deep vein thrombosis after hip surgery.

The authors report the results of a randomised double-blind study comparing the antithrombotic activity of a new anti-platelet drug (Triflusal) with that of acetylsalicylic acid (ASA). 99 patients who underwent hip surgery were included in the study (total hip replacement, osteosynthesis of a pertrochanter fracture or Moore's prosthesis for intracapsular fracture of the femoral neck). Of the 48 patients having received Triflusal, 7 (14.5%) developed deep vein thrombosis as indicated by 125I-fibrinogen isotopic scanning and confirmed by phlebography. Of the 51 patients treated with ASA, 11 (21.6%) presented the same complication as diagnosed by the same techniques. This difference is not statistically significant, considering the number of cases studied. Nevertheless, Triflusal appears to provide prevention of thromboembolic risk to patients who have undergone hip surgery, particularly total hip replacement.

[Osteosynthesis of lesions of the proximal femur using dynamic screw plates. Multicenter study: 1871 cases]. / Ostéosynthèse des lésions proximales du fémur par vis-plaque dynamisée. Etude multicentrique: 1871 cas.

A series of 1871 lesions of the upper end of the femur were treated in 32 hospitals in Belgium using a dynamic hip screw. Unstable pertrochanteric fractures were present in 34.4%. The remainder were intracapsular, extracapsular and subtrochanteric fractures, or tumour deposits. The patients were elderly, infirm and usually female. A fortnight after operation 89% were sitting, 64% could walk with a frame and 31% with crutches. Failure of fixation occurred in 3.6% of cases overall, with 6.6% in unstable fractures. Perioperative screw compression did not appear helpful, since most fractures settled after operation.