Phosphomevalonate kinase regulates the MVA/MEP pathway in mango during ripening.

Mango is a popular tropical fruit with a great diversity in taste and aroma, contributed primarily by terpenoids. Phosphomevalonate kinase (PMK) is a key enzyme for isoprenoid biosynthesis in the mevalonic acid (MVA) pathway responsible for terpenoids. In this study, two cultivars of mango, "Dashehari" and "Banganpalli", showing opposite spatio-temporal patterns of ripening polarity, were investigated for studying the role of MiPMK in aroma production. MiPMK transcription and enzyme activity increased during ripening in both varieties. Expression in the early-ripening inner zones preceded that in the later-ripening outer zones of "Dashehari" while it was higher in the early ripening outer zones in "Banganpalli". Polypeptide sequences of the two enzymes showed differences in a few amino acids that were also reflected in kinetic properties such as specific activity and pH optima. Silencing of MiPMK in "Dashehari" fruit by VIGS suppressed the kinase activity and led to changes in relative contributions of the mevalonic acid (MVA) and methylerythritol 4-phosphate (MEP) pathways. This also altered the fruit metabolite profile with a reduction/disappearance of sesquiterpenes such as geranyl geraniol, trans-farnesol, ß-caryophyllene, ß-pinene, bisabolene and guaiane but the appearance of menthol and d-limonene in silenced fruit. The study shows that MiPMK levels may control downstream metabolite flux of the MVA pathway in mango.

Dupuytren's disease: A reality in Black Africa.

Long regarded as a disease exclusively found amongst Northern Europeans, Dupuytren's disease was seldom studied amongst Black Africans. Thus, we sought to study the impact of Dupuytren's disease, its etiological, clinical and evolutionary peculiarities on a segment of the Senegalese population. This study analyzed data derived from clinical observations carried out between January 2006 and December 2018. It involved Senegalese subjects with Dupuytren's disease, the patients' history, profession, habitus, clinical findings, therapeutic modalities and disease staging. The population included 20 men and 6 women averaging 63.5 years of age (range 45-77). None of the patients reported a family of Dupuytren's disease. Twelve patients had diabetes, 11 were smokers and 22 were engaged exclusively in manual labor. The condition was bilateral in 14 cases. Tubiana stages N, I, II, III and IV were found in 31, 15, 9, 5 and 6 rays, respectively. Conservative treatment was done in 11 patients. Surgical treatment was carried out in the other 15 patients: needle fasciotomy (N=10) including two bilateral involvement and open fasciectomy (N=7). Functional outcomes were satisfactory. Lesions were all stable in the short and medium term. Two patients had progressive lesions on a longer-term basis. Dupuytren's disease is real among Afro-descendants from Senegal even though it is seldom studied. Based on the patients' recollection of Dupuytren's disease in their families, heredity is not yet a proven factor. The early forms are more common, and the lesions remain stable for a long time.

Modified Dunn osteotomy using an anterior approach used to treat 26 cases of SCFE.

INTRODUCTION: Osteotomy performed below the femoral neck plays a leading role in the treatment of slipped capital femoral epiphysis (SCFE). It results in anatomical reduction. Several modifications have been made to Dunn's original osteotomy technique. We have developed another modification to this technique that uses an anterior surgical approach on a traction table with fluoroscopy control. HYPOTHESES: Will this technique help to reduce the number of complications? Will its results be superior to those achieved with the standard Dunn osteotomy procedure? MATERIAL AND METHODS: This was a retrospective single-center study of 26 cases in 24 patients (2 bilateral cases). Patients were positioned supine on a traction table with fluoroscopy control. An anterior surgical approach was used. A trapezoid-shaped osteotomy was performed below the femoral head. The head's reduction was checked on the fluoroscope and the fixation confirmed. The Postel Merle d'Aubigné (PMA) score was used for the clinical assessment. The radiographic assessment was based on Southwick's angle. RESULTS: The mean slip angle of the femoral head was 57°. A mean correction of 47° was achieved. Based on the PMA score, good and excellent results were achieved in 20 cases (77%) and poor results occurred in 6 cases (23%). The surgical treatment had a significant effect on the PMA score (P=0.0008). In terms of complications, there were five cases of chondrolysis and one case of necrosis associated with chondrolysis. DISCUSSION: The anterior approach provides direct access to the femoral neck, and thereby a cautious osteotomy at the site of the slip itself. Use of a traction table makes the external manipulations, reduction and fixation procedures easier to carry out. The results of this study were comparable to published results. LEVEL OF PROOF: IV, retrospective treatment study.

[Surgery in black grain mycetoma: about 44 patients treated at aristide le dantec hospital (Dakar, Senegal) from December 2008 to March 2013]. / Chirurgie des mycétomes fongiques à grain noir. À propos de 44 patients pris en charge à l'Hôpital Aristide le Dantec de Dakar (Sénégal) de décembre 2008 à mars 2013.

Black-grain mycetomas are fungal and cannot be healed by antifungals only.We conducted this study to determine the interest of carcinologic surgery only in the management of those black-grain mycetomas.We led a retrospective study concerning 44 patients over a period of 52 months. The mean age of patients was 32.5 years. The main location of mycetomas was the foot (21 cases), the ankle (10 cases), the knee (8 cases), the leg (3 cases), the chest, the back and the pulp of the fourth finger once each. The bone was affected in 21 cases. The surgery consisted in a carcinologic excision or amputation depending on the extension of the lesion and the degree of bony infringement, with ganglionic cleaning out in case of lymphadenopathy. In the average retrospect of 25.5 months, we noted 8 cases of recurrences among which 2 on the amputated patients and 6 on the patients treated by carcinologic excision. The surgery constitutes the main therapeutic issue of the fungal mycetomas.

[Thoracic tumor-like fungal mycetoma: interest of large surgery with terbinafine]. / Un mycétome fongique tumoral dorsal: intérêt de la chirurgie large associée à la terbinafine.

Fungal mycetoma are inflammatory pseudo-tumors of subcutaneous tissues and possibly bones due to exogenous fungi. They have a chronic course, often poly-fistulated with an emission of fungal grains. We report the case of a 65-year-old farmer with a thoracic fungal mycetoma discovered incidentally, associated with bone involvement. The diagnosis was confirmed by the positive culture to Madurella mycetomatis. The outcome was favorable with terbinafine 1g per day for 12 months associated with complete excision of oncologic type followed by a skin graft.

[Traditional bonesetter's gangrene of limb in children in Regional Hospital of Kaolack (Senegal)]. / Gangrène de membre à la suite d'un traitement traditionnel de fractures par attelle en bambou chez l'enfant à l'Hôpital régional de Kaolack (Sénégal).

Little published data exist on the morbidity and mortality associated with poor trauma care in developing countries. This report highlights our experience with iatrogenic limb gangrene related to fracture management by traditional bonesetters. Children with bonesetter's gangrene were identified from a prospectively recorded paediatric surgery database at the Regional Hospital of Kaolack in Central Senegal. 21 children were treated for bonesetter's gangrene during a 18-month period (January 2007 up to June 2008). The average age was 10 years (range, 5 to 15 years). Bonesetter's gangrene was more common in boys (90.5%) and occurred almost exclusively in children from rural areas where access to health care was limited. 16 children underwent proximal extremity amputation. Complications included one case of tetanus. Bonesetter's gangrene is a preventable complication that results from a failure of child health planners to recognize the importance of basic trauma care. Management of fractures should be considered an essential component of child health programs in developing countries.

Posterior approach for surgical treatment of neglected elbow dislocation.

INTRODUCTION: Neglected elbow dislocations often result in contracture and functional impairment. Surgical treatment is challenging because of the accompanying triceps retraction. We wanted to share our experience in treating these neglected dislocations using the posterior approach. PATIENTS AND METHODS: This was a consecutive, prospective study over a 4.5-year period (January 2003 to June 2007) that included all the patients who presented with a neglected elbow dislocation that was older than 21 days. We treated 22 patients (17 men, five women) with an average age of 22.8±8.2 years (range 14 to 46 years). The dislocations were 8.5±4.2 months old on average (range 2 to 17 months). Average elbow flexion was 46.0°±25.9° (10° to 90°) and the extension deficit was 19.5°±18.4° (0° to 60°) before the surgery. A paratricipital approach was used in all patients. In 14 patients, the dislocation was reduced without triceps lengthening. In eight patients, a V-Y plasty of the triceps muscle was required. RESULTS: The average follow-up was 21 months (range 12 to 30 months). The improvement in the overall range of motion was statistically significant. Average elbow flexion was 112.7°±13.3° (60° to 130°) and the extension deficit was 26.6°±17.0° (0° to 60°). The average Mayo Clinic Elbow Performance Index score was 86 (range 50 to 100), with 14 excellent, four good, two average and two poor results. Complications included three cases of ulnar nerve paresis, which subsided within three months, and one case of superficial infection. DISCUSSION: Although surgical treatment is challenging, the functional improvement in neglected elbow dislocations is outstanding. The best functional results can be expected when the triceps splitting approach to the elbow is not used. LEVEL OF EVIDENCE: IV.

[Latarjet procedure for recurrent anterior instability of the shoulder. Report of 41 cases]. / Traitement De La Luxation Anterieure Recidivante De L'Epaule Par La Technique De La Butee Osteoplastique Selon Latarjet. A Propos De 41 Cas.

AIMS: Evaluate the technique of Bristow-Latarjet in the treatment of the recurrent dislocation of the shoulder. PATIENTS AND METHODS: It was a continuous retrospective study on 46 cases selected in the CHU of Dakar over 11 years. From our criteria of inclusion, 41 patients were retained. There were 37 men for 4 women, whose average age at the time of the intervention was 29 years (extreme: 20 - 44 years). The management of the first episode was unsuited in 25 times. The average time of the first repetition was 10 months and its number varied between 5 and 36 episodes. The treatment of the recurrences was also misfit in 23 times. All our patients were treated according to the technique of Bristow-Latarjet. A standard immobilization Mayo clinic during 3 weeks was made with a systematic rehabilitation. The evaluation was done according to the scale of Constant with 45,6 months an average retreat. RESULTS: We found: 7 excellent cases (17%); 14 very good cases (34%); 9 good cases (22%); 6 average cases (15%); 5 bad cases (12%). Five cases of omarthrosis (3 types II and 2 types III of Samilson-Prieto) were found like two surface cases of sepsis. There was neither post-operative recurrence nor iatrogenic nervous attack. CONCLUSION: The recurrent anterior dislocation of the shoulder represents a frequent complication of primary dislocations of the shoulder touching especially young subjects. Stabilization by the anterior coracoid abutment according to the technique of Bristow-Latarjet led well represents one of the best techniques for its treatment.

[Femoral neck fracture complicating orthopedic reposition of a dislocated hip: four cases]. / Fracture du col fémoral compliquant la réduction orthopédique d'une luxation de hanche: á propos de 4 observations.

Posterior dislocation of the femoral head with fracture is an exceptional hip injury. Emergency reduction is required. Reposition into the acetabular cavity of the dislocated femoral head may not be feasible. Irreducibility, instability, and more rarely accidental fracture of the femoral neck may also occur. We encountered this latter complication in four patients and report here its frequency and mechanism and propose preventive therapeutic measures. Seventy dislocations and fracture-dislocations of the hip were treated in our unit from March 1997 to February 2003. Among these cases, fourteen hip dislocations were complicated by femoral head fractures. Fracture of the femoral neck occurred during reduction in four. All four cases occurred in men, mean age 49.7 years, who were traffic accident victims (drivers or passengers). There were two Pipkin IV fracture-dislocations and two Pipkin II. The first reduction, achieved under general anesthesia in an emergency setting, was performed by an orthopedic surgeon in one patient and a general surgeon in three patients. Arthroplasty was used to treat the femoral neck fracture in three patients and pinning in one. We reviewed retrospectively the clinical and imaging data before and after reduction. Sub-capital fracture situated 4.0 cm (mean, range 3.5-4.5 cm) from the lesser trochanter occurred in all four cases. The head remained attached above and posteriorly to the acetabulum and was rotated less than 90 degrees . The fragment remaining in the acetabulum was displaced in two cases. In one patient, the fracture-dislocation of the head was associated with a fracture of the posterior rim of the acetabulum. This complication appears to result from an abrupt inappropriate reduction movement. The neck fracture would occur when capsulomuscular retention of the femoral head is associated with a head defect which catches on the rim of the acetabulum during the reduction movement. Neck fracture during reduction of traumatic hip dislocation is a serious complication. Prevention of this iatrogenic event requires a slow, progressive reduction limiting the trauma to a minimum; first intention open surgery may be required in selected cases.

Procaspase-2S inhibits procaspase-3 processing and activation, preventing ROCK-1-mediated apoptotic blebbing and body formation in human B lymphoma Namalwa cells.

Procaspase-2S has been reported to selectively prevent membrane blebbing and apoptotic body formation in human monocytic-like leukemic U937 cells after etoposide (VP-16) treatment (Droin et al., Oncogene 20. 260-269, 2001). Here, we show that procaspase-2S overexpressed in human B lymphoma Namalwa cells inhibits procaspase-3 processing and activation, preventing cleavage and activation of Rho GTPase-associated ROCK-1 kinase. Failure of ROCK-1 activation in Namalwa cells correlates with a sustained delay in the appearance of membrane blebbing and apoptotic body formation after VP-16 treatment. Reciprocal coimmunoprecipitation experiments indicate that procaspase-2S binds to procaspase-3, but not procaspase-2L and -9 in untreated and VP-16-treated Namalwa cells. These data suggest that procaspase-2S-mediated anti-apoptotic effects are associated with inhibition of the processing and activation of procaspase-3 in VP-16-treated cells.

Caspase- and mitochondrial dysfunction-dependent mechanisms of lysosomal leakage and cathepsin B activation in DNA damage-induced apoptosis.

A lysosomal pathway, characterized by partial rupture of lysosomal membranes and cathepsin B activation, is activated during camptothecin (CPT)-induced apoptosis in U937 and Namalwa cancer cells. These lysosomal events occur simultaneously with mitochondrial permeabilization and caspase activation. In U937 cells, blocking mitochondrial permeability transition pore with cyclosporin A and bongkrekic acid reduces mitochondrial and lysosomal rupture, suggesting that lysosomal rupture may be dependent, in part, on mitochondrial disruption. Overexpressing bcl-xL, an antiapoptotic protein known to preserve mitochondrial functions, also impedes lysosomal and mitochondrial disruption in both cell lines, indicating signaling between the two organelles. In addition, no evidence was obtained of bcl-2-like proteins targeting lysosomes. Caspase activities, including caspase-2L, are required for lysosomal and mitochondrial disruption, and lysosomal cathepsin B slightly participates in apoptosis propagation after CPT, although not essential for apoptosis activation. Our study provides evidence for the participation of a lysosomal pathway during DNA damage-induced cell death. Our data suggest that caspase activation and mitochondrial disruption represent cell-context-specific mechanisms by which DNA damage leads to lysosomal rupture, and that lysosomal cathepsins could slightly participate in apoptosis propagation after CPT.

[Sternoclavicular dislocations: clinical and therapeutic study. A report of 9 cases]. / Luxations sterno claviculaires: aspects cliniques et thérapeutiques. A propos de neuf cas.

Sterno-clavicular dislocations represent an uncommon pathology in shoulder trauma. The authors describe the anatomical and clinical forms observed between January 1999 and December 2002, and evaluate the treatment process. The retrospective study addressed 9 patients (men only) with an average age of 26.6. Based on the duration of the consulting period, one could distinguish old forms from more recent ones. Diagnosis would help to see anterior forms from posterior forms. Evaluation criteria were: pain, mobility of the shoulder, visibility of the deformation of the sterno-clavicular joint. Six types of anterior dislocations were listed, including 4 recent and 2 old ones. There were 3 recent posterior forms. The anterior recent forms, which were treated in orthopedics, showed a positive evolution. As there was no functional disability, it was wiser to refrain from any treatment of the anterior old forms. The posterior forms, two of them were operated (osteosynthesis) revealed no functional deficit after treatment. However, one of the patients had a broken implant. Scanner facilitated the diagnosis of sterno-clavicular dislocations. The anterior forms, which are more frequent and benign, are different from the posterior forms, which are emergency cases due to the proximity of the aero-digestive and cardiovascular elements. Their surgical stabilization requires techniques related to ligamentoplasty rather than using osteo-synthesis equipment which may move away or break off.

Caspase inhibition in camptothecin-treated U-937 cells is coupled with a shift from apoptosis to transient G1 arrest followed by necrotic cell death.

Leukemia U-937 cells rapidly undergo characteristic morphological changes, caspase activation, and DNA fragmentation typical of apoptosis on treatment with the DNA topoisomerase I inhibitor camptothecin (CPT). In a previous report (Sané, A. T., and Bertrand, R., Cancer Res., 58: 3066-3072, 1998), we showed that, after CPT treatment, caspase inhibition by the tripeptide derivative benzyloxycarbonyl-Val-Ala-Asp(Ome)-fluoromethyl ketone (zVAD-fmk) blocked apoptosis and slowed passage of the cells through S-G2 and caused a transient accumulation of these cells at the G1 phase of the cell cycle. Accumulation of these cells at G1 is not associated with major changes in expression level of cyclin-dependent kinase (cdk)2, cdk4, and cdk6; cyclin D1 and cyclin E; or p16, p21, p27, and p57 after CPT treatment. Furthermore, cdk2, cdk4, and cdk6 kinase activities remain unaffected after CPT treatment. These results indicate that the G1 arrest of these cells does not correlate with a classical driven cell cycle checkpoint but with the known effect of CPT in mediating inhibition of DNA replication and RNA transcription after stabilization of topoisomerase I-linked DNA strand breaks. However, persistent caspase inhibition after CPT treatment also results in cells falling into necrosis after the transient G1 arrest. These results indicate that the enforced inhibition of caspase activities does not confer a survival advantage upon CPT-treated cells but is coupled with a shift from apoptosis to transient G1 arrest followed by massive necrosis.

Effect of renal transplantation (surgical stress) on serum levels of oxidants and reducing system.

BACKGROUND: This study attempts to understand the correlation (if any) between surgical stress of renal transplantation and serum levels of pro-oxidant/antioxidants. METHODS: Twenty-four ESRD patients having undergone transplant surgery followed from day-1 to day-10 postsurgery were investigated for serum levels of MDA, SOD, Vit. C and E. The drug regimen received was immunosuppressant, H2 blockers and antihypertensives as per the situation. RESULTS: The typical observations indicated elevated serum levels of MDA from preoperative stage reaching peak value 24 hrs after surgery followed by a steady fall and achieving minima on the 10th day. As regards antioxidants enzyme SOD, Vit. C, Vit. E were low from pretransplant day reaching minima 24 hours postoperatively and returning to normal from 7th day. CONCLUSIONS: The present investigation has amply shown a typical imbalance between pro-oxidant/antioxidants from pretransplant day up to 24 hrs and there after returning to normal level from 7th day suggestive to desired recovery and surgical stress not a limiting factor in way of health progress renal transplant. Dietary intake of Vit. C and E in mega doses can be a good therapeutic measure.

Distinct steps in DNA fragmentation pathway during camptothecin-induced apoptosis involved caspase-, benzyloxycarbonyl- and N-tosyl-L-phenylalanylchloromethyl ketone-sensitive activities.

Monocytic-like leukemia U-937 cells rapidly undergo morphological changes and DNA fragmentation that is typical of apoptosis following treatment with DNA topoisomerase I inhibitor [20-S-camptothecin lactone (CPT)]. The tripeptide derivative benzyloxycarbonyl-Val-Ala-Asp(OMe)fluoromethyl ketone blocks Asp-Glu-Val-Asp-ase (DEVDase) activity and prevents the occurrence of high molecular weight and oligonucleosome-sized DNA fragments associated with apoptosis in CPT-treated cells. In contrast, N-tosyl-L-phenylalanylchloromethyl ketone (TPCK) does not prevent DEVDase activity and high molecular weight DNA fragmentation but completely abrogates the appearance of oligonucleosome-sized DNA fragmentation. These results suggest that caspase 3-like activities are involved with high molecular weight DNA fragmentation pathway, whereas TPCK-sensitive activities are involved in oligonucleosome-sized DNA fragmentation pathway in CPT-treated cells. Electron micrographs reveal that caspase inhibition by benzyloxycarbonyl-Val-Ala-Asp(OMe)fluoromethyl ketone also abrogates the typical morphological changes associated with apoptosis, whereas TPCK does not delay these morphological changes that are typical of apoptosis. Caspase inhibition slows passage of the cells through G2 and causes a transient accumulation of these cells at the G0/G1 phase of the cell cycle following CPT treatment. In a cell-free system, when purified nuclei are incubated with apoptotic cytosolic extracts obtained from CPT-treated U-937 cells, TPCK causes a similar effect in abrogating the oligonucleosome-sized DNA fragmentation but does not affect DEVDase activity. Addition of either benzyloxycarbonyl-Val-Ala-Asp-free carboxyl group or acetyl-Asp-Glu-Val-Asp-aldehyde completely inhibits DEVDase activity in these extracts. However, acetyl-Asp-Glu-Val-Asp-aldehyde does not affect the occurrence of oligonucleosome-sized DNA fragmentation in the cell-free system, whereas the benzyloxycarbonyl derivatives benzyloxycarbonyl-Val-Ala-Asp-free carboxyl group, benzyloxycarbonyl-Val-Ala-free hydroxyl group, benzyloxycarbonyl-Val-free hydroxyl group, and benzyloxycarbonyl hydrazide abolish it markedly. Taken together, these observations show the pivotal role of DEVDase activity in triggering the apoptotic process and high molecular weight DNA fragmentation, whereas TPCK- and benzyloxycarbonyl-sensitive activities are involved in the oligonucleosome-sized DNA fragmentation pathway induced by CPT.

[Epidemiological and clinical aspects of pancreatic cancer in Senegal]. / Aspects épidémiologiques et cliniques du cancer du pancréas au Sé négal.

The objective was to verify if the introduction of ultrasonography in our practice has entailed modifications of the epidemiology and the clinic of pancreatic cancer in Senegal. We have performed a retrospective study of cancer of the pancreas diagnosed on the basis of clinical signs, ultrasonography, surgical findings and necropsy from March 92 to October 97. The chi-square test according to Mantel-Haenszel has been used to compare qualitative variables. The routine practice of ultrasonography has allowed to establish the diagnosis of 107 cases of pancreatic cancer within 5 years and half. The sex ratio was 1.05 and the average age was 60 years +/- 13 without significant difference according to the sex. The mean period of diagnosis was 5 months. However the classic form associating thinness and cholestatic jaundice or palpable abdominal mass dominated the clinical symptoms (74.5% of cases). A very deep alteration of the general status has been noticed in 25.5% of cases. At surgery, according to the TNM classification, 22% of our patients were at stage II and 78% from stage III to IV. In Senegal, the prevalence of pancreatic cancer is increasing since the introduction of ultrasonography. This technique has shown that the male predominance is less than reported in previous studies. Nevertheless the diagnosis remains late. As far as we cannot identify risk groups, recent appearance of digestive disturbance even atypical after 50 years old, is enough to suspect the diagnosis.

Oxidative stress status in children with nephrotic syndrome.

In continuation of our work on human stress situation and present day awareness of the role of free radical toxicity in a variety of clinical conditions, oxidative stress status (in terms of serum levels of MDA, scavenging enzyme SOD, vitamins: C and E) has been studied in 45 pediatric patients with nephrotic syndrome (further classified as steroid: responders, frequent/ infrequent relapsers, dependents). The results have been compared with 42 appropriately age healthy children as controls. The salient features of the present study centre around typical observations viz significantly increased levels of MDA (7.92 +/- 2.24 nmol/ml), decreased levels of SOD (1.36 +/- 1.01 U/ml), vitamin C (0.49 +/- 0.17 mg/dl) and vitamin E (0.52 +/- 0.19 mg/dl) in children with nephrotic syndrome as a whole when compared with healthy controls [MDA (4.40 +/- 1.31 nmol/ml), SOD (3.04 +/- 1.83 U/ml), vitamin C (0.60 +/- 0.26 mg/dl) and vitamin E (0.68 +/- 0.25 mg/dl) respectively]. An almost similar trend was encountered in different groups as classified. However, maximum fluctuations were observed in steroid dependents. The present observations appear to be suggestive of alternative guidelines to clinicians in the absence of conventional renal biopsy as the procedure. It is felt that children with nephrotic syndrome should regularly take vitamins C and E from the health point of view.

The Bcl-xL and Bax-alpha control points: modulation of apoptosis induced by cancer chemotherapy and relation to TPCK-sensitive protease and caspase activation.

Defective control of apoptosis appears to play a central role in the pathogenesis of human diseases including neoplasic, autoimmune, and neurodegenerative diseases. Conversely, cancer chemotherapy and ionizing radiation can induce cancer cell death by apoptosis, and deregulated apoptosis following cancer chemotherapy could define a new category of drug resistance mechanism. By understanding the role that some major regulators of apoptosis play either at the commitment or execution phases of cell death in a given tissue and pathology, we will be in a better position to design and explore new therapeutic modalities. The Ced-9 - Bcl-like and Ced-3 - Ice-like gene family products are intrinsic proteins regulating the decision of a cell to survive or die and executing part of the cell death process itself, respectively. Among the various Bcl-like proteins, the effects and functions of the Bcl-x and Bax proteins in controlling apoptosis induced by cancer chemotherapy have been studied recently. In human cancer variant cell lines showing differential expression of the Bcl-xL protein, a preventive effect of Bcl-xL on cell death induced by various cytotoxic drugs is observed, with greater effects in cells containing the highest level of Bcl-xL expression. Similarly, overexpression of Bax-alpha in cancer cell lines sensitizes these cells to some cancer chemotherapy compounds. Modulation of apoptosis either negatively by Bcl-xL or positively by Bax-alpha resides downstream of the primary mechanism of action of anticancer drugs, suggesting that they act primarily as intrinsic control points following cytotoxic drug injuries. An emerging family of Ced-3 - Ice like cysteine proteases (caspases) has been also identified and several studies have revealed their importance in executing the process of cell death. More recently, activation of a N-tosyl-L-phenylalanylchloromethyl ketone (TPCK)-sensitive pathway was also suggested to play an important role in apoptosis induction following cancer chemotherapy. Evidence obtained using a combination of assays including cell-free systems and enzyme activity assays now suggests that Bcl-xL and Bax-alpha control points function upstream of TPCK-sensitive protease and caspase activation. Bcl-xL delays and prevents activation of apoptotic protease cascades whereas Bax-alpha shows the opposite effect, accelerating their activation.