Enhanced Kidney Damage Induced by Increasing Nonylphenol Doses: Impact on Autophagy-Related Proteins and Proinflammatory Cytokines in Rats.

Nonylphenol (NP) is an organic pollutant and endocrine disruptor chemical that has harmful effects on the environment and living organisms. This study looked at whether kidney tissues subjected to increasing doses of nonylphenol generated alterations in histopathologic, pro-inflammatory, and autophagic markers. Fifty rats were divided into five groups of ten each: group I: healthy group, II: control (corn oil), group III: 25 µl/kg NP, group IV: 50 µl/kg NP, group V: 75 µl/kg NP. The kidney tissue samples were obtained for histopathological, immunohistochemical, and biochemical analyses. The histological deteriorations observed in all NP groups included tubular epithelial cell degeneration, inflammation areas, and hemorrhage. The immunohistochemical investigations showed that NP significantly elevated the autophagy markers (Beclin-1, LC3/2, p62), pro-inflammatory cytokines (TNF-α, IL-6), HIF-1α, and eNOS in group III, IV and V compared with group I and II. The biochemical analysis also revealed that pro-inflammatory cytokines (TNF-α, IL-1ß, and IL-6) increased in correlation with the NP doses, but only IL-1ß reached statistical significance in NP treated rats kidney tissue. The biochemical findings have been confirmed by the histological studies. The damage to renal tissue caused by NP exposure may worsen it by increasing inflammatory and autophagic markers.

Role of apoptosis and autophagy in folic acid-induced cytotoxicity of human breast cancer cells in vitro.

Obstacles to the successful treatment of breast cancer patients with chemotherapeutic agents can be overcome with effective new strategies. It is still unclear how folic acid affects the onset and spread of breast cancer. The purpose of this study was to determine how folic acid affected the apoptotic and autophagic pathways of the breast cancer cell lines MCF-7 and MDA-MB-231. In the present study, folic acid was applied to MCF-7 and MDA-MB-231 breast cancer cell lines at different concentrations and for different durations. MTT analysis was used to investigate cytotoxic activity. All groups underwent the Tunel staining procedure to identify apoptosis and the immunofluorescence staining approach to identify the autophagic pathway. 24-hour folic acid values were accepted as the most appropriate cytotoxic dose. In MCF-7, cell cycle arrest was observed in the S phase and MDA-MB-231 G1/G0 phases. When apoptotic TUNEL staining was evaluated in both cell lines, folic acid significantly increased apoptosis. While a significant difference was observed between the groups in terms of Beclin 1 immunoreactivity in the MDA-MB-231 cell line, there was no significant difference in the MCF-7 cell line. In addition, statistical significance was not observed LC3 immunoreactivity in both cell lines. In the study, it was observed that folic acid induced autophagy at the initial stage in the MDA-MB-231 cell line but had no inductive effect in the MCF-7 cell line. In conclusion, our findings showed that folic acid has a potential cytotoxic and therapeutic effect on MCF-7 and MDA-MB-231 breast cancer cell lines.

Protective Effects of Boric Acid Taken in Different Ways on Experimental Ovarian Ischemia and Reperfusion.

Ovarian ischemia is a gynecological emergency that occurs as a result of ovarian torsion, affects women of reproductive age, and reduces ovarian reserve. The current study was designed to investigate the effect of boric acid taken in different ways on histopathological changes, autophagy, oxidative stress, and DNA damage caused by ischemia and reperfusion in the ovary of adult female rats. We established seven groups of 70 adult female rats: untreated control, intraperitoneal boric acid group (IpBA), oral boric acid group (OBA), ischemia/reperfusion group (ischemia/2 h reperfusion; OIR), ischemia/reperfusion and local boric acid group (OIR + LBA), ischemia/reperfusion and intraperitoneal boric acid group (OIR + IpBA), and ischemia/reperfusion and oral boric acid group (OIR + OBA). On the 31st day of the experimental procedure, both ovaries were harvested for histologic (hematoxylen and eosin and Masson trichrom), biochemical (ELISA and AMH, MDA, SOD, and CAT analyses), and comet evaluation. In the OIR group, hemorrhage, edema, inflammation, and diminished follicle reserve were seen in the ovary. Boric acid treatment reduced the ovarian ischemia/reperfusion damage, and the follicles exhibited similar morphological features to the control group. Moreover, boric acid treatment decreased the levels of Hsp70, NF-KB, COX-2, and CD31, which increased as a result of OIR. On the other hand, SCF and AMH levels, which decreased as a result of OIR, increased with boric acid treatment. The levels of autophagy markers (Beclin-1, LC3, and p62) reached values close to those of the control group. According to the biochemical findings, it was concluded that boric acid is also effective on oxidative stress, and the AMH level was particularly high in the OIR + OBA group, consistent with the immunohistochemical staining result. In addition, it was observed that the DNA damage caused by OIR reached values close to those of the control group, especially in the OBA after OIR. This study showed the therapeutic effects of boric acid on OIR injuries; thus, boric acid may be a potential therapeutic agent for ovarian protection and fertility preservation in cases that may cause ovarian torsion.

Anti-inflammatory and pro-regenerative effects of a monoterpene glycoside on experimental periodontitis in a rat model of diabetes.

OBJECTIVE: Paeoniflorin (Pae) is a monoterpene glycoside with immune-regulatory effects. Several studies have already demonstrated the impact of Pae on periodontitis, but its effect on diabetic periodontitis is unclear. In this study, our aim was to test the hypothesis that Pae had a strong anti-inflammatory effect that prevented bone loss in diabetic periodontitis. METHODS: Thirty male Wistar albino rats were randomly divided into control (healthy, n = 10), periodontitis (PD) + diabetes (DM; n = 10), and PD + DM + Pae (n = 10) groups. Ligature-induced periodontitis was created by placing 4-0 silk ligatures around the lower first molars on both sides of the mandibulae. Experimental DM was created via an injection of 50 mg/kg and streptozotocin (STZ). Hyperglycemia was confirmed by the blood glucose levels of rats (>300 mg/dL). The bone mineral density (BMD), trabecular number, trabecular thickness, and bone loss were measured by micro-CT. The expression levels of IL-1ß, IL-6, and TNF-α were measured in tissue homogenates by ELISA. RESULTS: The PD + DM + Pae group had significantly less alveolar crest resorption when compared to the PD + DM group. There was also a significant difference between the PD + DM + Pae group compared to PD + DM group in trabecular thickness, BMD, and the number of trabeculae. Pae application led to a statistically significant decrease in IL-1ß, IL-6, and TNF-α levels in diabetic periodontitis. CONCLUSION: Systemic application of Pae suppressed inflammation caused by PD and DM, leading to reduced bone loss and enhanced bone quality.

The effect of different doses of nonylphenol on the blood-testicular barrier integrity, hormone level, and DNA damage in the testes of rats.

Determining the molecular characteristics of the damage caused by NP exposure in the testis is very important for understanding the source of the damage and developing treatment methods accordingly. Therefore, in this study, it is aimed to evaluate the toxic effects that different doses of NP may cause in the testis, including blood-testicular barrier integrity and sperm DNA damage. For this purpose, 50 adult male Wistar albino rats were used in the study. Low, medium, and high-dose NP groups and the corn oil group were formed. After NP administration at determined doses for 15 days, the testis tissue taken under anesthesia was fixed in formaldehyde. Paraffin blocks were embedded using the routine histological tissue follow-up method. Histopathological and immunohistochemical analyses were performed by taking 5 µm thick sections from paraffin blocks. The other testicular tissue was taken for the Western blot, Elisa, and comet methods, and the findings of sperm DNA analysis and the blood-testicular barrier were examined. NP caused the seminiferous epithelium to be disorganized and have significantly fewer cells in the testes of rats in different dose NP-induced groups. Compared with the control group, mTOR, Cx43, SCF, and HSP70 protein levels were decreased, while the expression of MMP-9 levels was increased in the different NP dose groups. Furthermore, tissue testosterone and inhibin B levels and SF-1 immunoreactivity intensity gradually decreased depending on the dose increase of NP. DNA damage of testicular tissues were increased in NP groups depending on NP dose. These results suggest that it is evident that NP, a commonly used industrial chemical, is an endocrine disrupting chemical (EDC) with estrogenic activity exerting adverse effects on health and that urgent measures are needed regarding the use.

Nonylphenol Exposure-Induced Oocyte Quality Deterioration Could be Reversed by Boric Acid Supplementation in Rats.

In this study, we reported boric acid's protective effects on the quality of nonylphenol (NP)-exposed oocytes. Female rats were classified into 4 groups: control, boric acid, NP, and NP+boric acid. Histopathological studies and immunohistochemical analysis of anti-müllerian hormone (AMH), mechanistic target of rapamycin (mTOR), Sirtuin1 (SIRT1), stem cell factor (SCF) studies were done. The comet assay technique was utilized for DNA damage. The ELISA method was used to determine the concentrations of oxidative stress indicators (SOD, CAT, and MDA), ovarian hormone (INH-B), and inflammation indicators (IL-6 and TNF-α). Boric acid significantly reduced the histopathological alterations and nearly preserved the ovarian reserve. With the restoration of AMH and SCF, boric acid significantly improved the ovarian injury. It downregulated SIRT1 and upregulated the mTOR signaling pathway. It provided DNA damage protection. Ovarian SOD, CAT levels were decreased by boric acid. Boric acid co-administration significantly reduced NP's MDA, IL-6, and TNF-activities. This results imply that boric acid has a protective role in ovarian tissue against NP-mediated infertility.

Therapeutic potential of hesperidin: Apoptosis induction in breast cancer cell lines.

Hesperidin is a flavonoid commonly found in citrus fruits. Studies have shown that hesperidin has anti-inflammatory, analgesic, and antimicrobial properties, as well as its effectiveness in carcinogenesis. In this paper, we aim to investigate the molecular mechanisms of hesperidin-induced apoptosis in MCF-7 and MDA-MB-231 cancer cells. The inhibitory effect of hesperidin on cellular proliferation was evaluated with the MTT assay. Cell cycle analysis of hesperidin-treated cells was then performed, as well as immunocytochemical analysis of the effect on the apoptosis pathway (TUNEL, Bax, and Bcl-2 expression). Moreover, hesperidin induced cellular apoptosis in MCF-7 breast cancer cells by inhibiting Bcl-2 and enhancing Bax expression at protein levels. On the other hand, hesperidin caused apoptosis in the MDA-MB-231 breast cancer cell line, but it did not activate the Bax/Bcl-2 pathway. Hesperidin also induced cell cycle arrest at the S phase in the MCF-7 and MDA-MB-231 cell lines. These findings showed that hesperidin is a potential therapeutic candidate for preventing the progression of breast cancer. In addition, hesperidin could significantly stimulate the death mechanisms in ER/PR (+) MCF-7 cells by changing the expression balance of Bax and Bcl-2 proteins, but lead ER/PR (-) MDA-MB-231 breast cancer cells to apoptosis in a different way.

The role of cur ole of curcumin against paclitax cumin against paclitaxel-induced o el-induced oxidativ xidative stress and DNA damage in testes of adult male rats.

BACKGROUND: Paclitaxel is a widely used drug for the treatment of cancer, but it possesses toxic effects on male reproductive system. Administering paclitaxel with an antioxidant has become a strategy for preventing the side effects of paclitaxel. Although curcumin is an antioxidant, data concerning the effect of curcumin on paclitaxel-induced testis tissue are lacking. The present study was established to examine the protective impact of curcumin against testicular damage induced by paclitaxel. METHODS: In the study, 40 Wistar albino male rats were used and randomly divided into 4 groups (n:10). The control group received only saline solution; the curcumin group received curcumin throughout the experiment; the paclitaxel group received a total of four doses of paclitaxel on days 1, 7, 14, and 21 of the experiment; curcumin + paclitaxel group received curcumin throughout the experiment and a total of four doses of paclitaxel on days 1, 7, 14, and 21 of the experiment. At the end of the experiment, the rats were decapitated under xylazine and ketamine anesthesia and their testicles were removed. The sections obtained from the testicles were stained with Hematoxylin & Eosin and histopathological damage was evaluated. The TUNEL method was applied to determine apoptotic cells. Testosterone levels were measured in the blood serum. The Johnsen testicular biopsy score (JTBS) was used to evaluate testicular tubules. DNA damage was evaluated in sperm samples taken from the ductus epididymis using the comet assay technique. RESULTS: Testicular tissue was severely damaged in the paclitaxel group. In the curcumin + paclitaxel group, it was determined that the administration of curcumin with paclitaxel reduced the histological damage in the testicular tissue. Moreover, according to the JTBS, the value was significantly higher in the testicular tubules (p < 0.05). Testosterone levels were higher in curcumin + paclitaxel group than in paclitaxel group. DNA damage also decreased significantly in curcumin + paclitaxel group when compared to paclitaxel group (p < 0.05). DISCUSSION: The results showed that curcumin may be protective against damage caused by paclitaxel in the testicles of rats.

Protective effects of melatonin on female rat ovary treated with nonylphenol.

We investigated using histochemistry and immunohistochemistry ovarian damage caused by nonylphenol (NP) and the protective effect of melatonin treatment of NP induced ovarian damage. We used 21 female rats divided randomly into three groups: control, NP and melatonin + NP. Histopathological examination of the ovaries, and counting and classification of follicles were performed using Masson's trichrome staining. Expression of anti-Mullerian hormone (AMH), Bax, Bcl-2 and caspase-3 was detected in the ovaries using immunohistochemistry. Melatonin had an ameliorative effect on NP induced follicular atresia and absence of corpora lutea. More follicles were observed in the ovaries of animals treated with melatonin prior to treatment with NP. AMH immunoreactivity was significantly lower in the NP group than in the melatonin + NP group. NP increased immunostaining for Bax, Bcl-2 and caspase-3. Melatonin significantly reduced the increased expression of Bax, Bcl-2 and caspase-3 due to NP exposure. We found that pretreatment with melatonin is beneficial for protecting the ovaries from damage by NP.

Bone development in offspring of pregnant rats treated with carbamazepine: Evaluation by three different methods.

OBJECTIVE: This study was carried out to determine the effect of intrauterine carbamazepine (CBZ) exposure on fetal bone development during pregnancy. METHODS: In the study, 24 female Wistar pregnant rats were used. Rats were 20 weeks old. They had an average body weight of 150-200 g. Pregnant rats were randomly selected and divided (n = 6) into a control group, low-dose CBZ (10 mg/kg/day) group, medium-dose CBZ (25 mg/kg/day) group, and high-dose CBZ (50 mg/kg/day) group. The ossification length (mm) and ossification area (mm2 ) of the long bones of the fetuses in the experimental and control groups were calculated. The densities of alkaline phosphatase (AP) and tartrate-resistant acid phosphatase (TRAP) were analyzed. The ossification regions of the femurs of the fetuses were examined under a light microscope. Microstructural images of the femurs were evaluated with scanning electron microscope photographs. The densities of minerals involved in the ossification process were analyzed. RESULTS: According to the results of the study, all three doses of CBZ caused loss of ossification areas, and it was observed that this bone loss also increased statistically significantly depending on the dose increase (p < .05). Calcium concentration decreased in the CBZ groups. When the electron microscope images were examined, it was determined that the cartilage matrix of the CBZ groups was thinned. In the histological evaluation of the groups, narrowing of the primary bone collar and smaller bone spicules in the ossification region compared to the control group were noted due to the increase in dose in the CBZ groups. In immunohistochemical staining, it was observed that the TRAP and AP expression values of the femurs were the lowest in the CBZ groups. These decreases were also statistically significant when compared with the control group. SIGNIFICANCE: It was revealed with both microscopic and macroscopic findings that exposure to intrauterine CBZ negatively affected ossification and bone growth.

Effect of Photobiomodulation Therapy on Peri-Implant Bone Healing in Extra-Short Implants in a Rabbit Model: A Pilot Study.

Objective: To evaluate the effects of photobiomodulation therapy (PBMT) at distinct energy levels on peri-implant bone healing in extra-short implants in a experimental rabbit model. Background: The effect of PBMT on peri-implant bone healing in short implants remains unclear. This explored the effect of PBMT on extra-short implants in terms of bone-implant contact (BIC) length and rate, and implant stability quotient (ISQ). Methods: Fifteen white New Zealand rabbits were randomly divided into five groups. In all groups, extra-short implants (3.5 × 4 mm; Nucleoss T6, Izmir/Turkey) were placed in both tibias of the rabbits. PBMT was performed in four groups (group 1, 5 J/cm2; group 2, 10 J/cm2; group 3, 20 J/cm2; and group 4, 25 J/cm2); no PBMT was performed in the control group. On the 30th day, the rabbits were sacrificed and peri-implant tissue samples were obtained to determine the BIC length and BIC rate. Implant stability levels were measured by resonance frequency analysis using the Osstell penguin device and were determined as ISQ values on the 1st and 30th days of the study. Results: PBMT significantly increased the BIC length and BIC rate in groups 3 and 4 (p < 0.001). For the ISQ values, there were significant differences between the 1st and 30th day (p < 0.001). On the 30th day, the ISQ values were significantly higher in groups 3 and 4 compared with the remaining groups (p < 0.001). Conclusions: In this study, PBMT improved peri-implant bone healing through increase in BIC length, BIC rate, and ISQ parameter values in extra-short implants.

Surgical Procedures Required for Measurement Reduce Nerve Conduction Velocity: An In Vivo and In Vitro Comparative Study.

Background: Although in vitro methods have disadvantages, they are still commonly used to measure nerve conduction velocity (NCV) in experimental studies. Therefore, this study was designed to demonstrate the effect of the surgical procedures required for in vitro methods on nerve fibers and the effect of in vivo and in vitro methods on the results of electrophysiological measurements.Methods: Rats were assigned to the in vivo (control-1, injury-1, and diabetic-1) and in vitro (control-2, injury-2, and diabetic-2) groups. The NCV and compound action potential amplitudes were measured, and the nerve fibers were histologically examined.Results: Damaged axons and myelin sheaths were observed in the control-2 group. The electrophysiological values of the in vitro groups were lower than those of the in vivo groups. Furthermore, these values were lower for the diabetic and injury groups than for the control groups.Conclusions: This study showed that the surgical procedures required for the in vitro method reduced the measured values. Owing to the previous and current disadvantages of the in vitro method, the in vivo method was more sensitive for the NCV measurement. Moreover, measurements can be performed using the current in vivo method for small nerve fibers.

Use of selenium to ameliorate doxorubicin induced hepatotoxicity by targeting pro-inflammatory cytokines.

Doxorubicin (DOX) is a widely used drug for the treatment of cancer,but its clinical use is limited by its liver toxicity. Administering DOX with an antioxidant has become a strategy for preventing the side effects of DOX. Although selenium (Se) is an important trace mineral, data concerning the effect of Se on DOX induced liver tissue are lacking. We investigated the mechanism of DOX hepatotoxicity and the protective effect of different doses of Se on Dox induced liver damage. Female Wistar albino rats were divided into eight equal groups. Se was injected intraperitoneally (i.p.) to rats at doses of 0.5, 1, and 2 mg 0.5 h after injection i.p. of 5 mg/kg DOX on days 1, 7, 14, 21 and 28. Liver histopathology was assessed to determine the dose at which Se may best inhibit Dox induced liver toxicity. Also, tumor necrosis factor-α (TNF-α), interleukin-1ß (IL-1ß) expression levels and proliferating cell nuclear antigen (PCNA) activity were determined using immunohistochemistry. We found that DOX caused liver damage and increased TNF-α, IL-1ß and PCNA levels. Se prevented structural damage to liver tissues. Our findings reinforce the protective effects of Se in rat liver.

Effects of 405-, 532-, 650-, and 940-nm wavelengths of low-level laser therapies on orthodontic tooth movement in rats.

BACKGROUND: Investigating the effects of 405-nm, 532-nm, 650-nm, and 950-nm wavelengths of LLLTs (low-level laser therapies) on the orthodontic tooth movement in rats by using histological and immunohistochemical methods. Forty-five Wistar albino rats were randomly divided into 5 groups: control group (positive control: the left maxillary 1st molar side; negative control: the right maxillary 1st molar side), 405 nm LLLT group (Realpoo), 532 nm LLLT group (Realpoo), 650 nm LLLT group (Realpoo), and 940 nm LLLT group (Biolase). The left maxillary 1st molar teeth of all rats were applied mesially 50-g force. Starting from the 1st day, 48 h intervals, LLLT was applied in continuous wave mode and in contact with the tissue. The application area was approximately 1 cm2. The lasers were performed for 3 min on each surface (buccal, palatal, mesial), totally 9 min (total dose 54 J/cm2). The amount of the molar mesialization, the bone area between the roots, PDL (periodontal ligament) measurements, TRAP (tartrate-resistant acid phosphatase), and ALP (alkaline phosphatase) immunoreactivity intensity were calculated. RESULTS: The amount of the molar mesialization was significantly higher in the 650 nm LLLT group (mean 0.878 ± 0.201 mm; 95% CI (confidence interval) 0.724 and 1.032) than in the groups of positive control (mean 0.467 ± 0.357 mm; 95% CI 0.192 and 0.741) and 405 nm LLLT (mean 0.644 ± 0.261 mm; 95% CI 0.443 and 0.845) (p < 0.001). There were significant differences in the PDL-mesial (p = 0.042) and PDL-distal (p = 0.007) regions between the groups. The immunoreactivity intensity for TRAP-mesial was significantly higher in the positive control group (mean 109,420.33 ± 8769.17; 95% CI 100,217.65 and 118,623.02) than in the 405 nm (mean 91,678.83 ± 7313.39; 95% CI 84,003.9 and 99,353.77) and the 650 nm LLLT (mean 87,169.17 ± 4934.65; 95% CI 81,990.56 and 92,347.77) groups (p = 0.002). There was no statistically significant difference between the groups on immunoreactivity intensity with ALP staining. CONCLUSIONS: The results of this study show that LLLT with 650-nm wavelength increases orthodontic tooth movement more than 405-nm, 532-nm, and 940-nm LLLTs. The 940-nm and 650-nm LLLTs also increase the bone area between the roots by more than 405-nm and 532-nm wavelengths.

Assessment of markers expressed in human hair follicles according to different skin regions.

BACKGROUND: Body region-dependent hair follicle (HF) characteristics are concerned with follicular size and distribution, and have been demonstrated to have characteristics for each region of the body. OBJECTIVES: The aim of the present study was to investigate the expression patterns of the markers called cytokeratin 15 (K15), cytokeratin 6 (K6) and monoclonal antibody Ki-67, and also apoptosis in HFs, which can be observed in different parts of the human body. MATERIAL AND METHODS: In this study, healthy human HFs were taken by biopsy from 5 various donor sites of the human body: the scalp, the leg, the abdomen, the back and waist. HF-containing skin specimens taken using cryosection were stained with hematoxylin & eosin (H&E) and K15, K6, Ki-67 and terminal deoxynucleotidyl transferase-mediated digoxigenin-dNTP nick end-labelling (TUNEL) immunofluorescence staining protocol was performed. RESULTS: Different skin regions from the human body were examined histologically. While the HFs of scalp tissue showed anatomically obvious hair layers, some hair sections from other regions, like the leg, the abdomen, back and waist, were not as distinct as in the scalp region. According to our findings, K15 expression was highest in the scalp. In addition, the immunoreactivity (IR) intensity of K15 was significantly decreased in the HFs on the waist and abdominal regions, compared to the scalp and back regions (p < 0.001). However, the IR intensity of K6 in the scalp region was statistically significantly higher than the IR intensity of K6 in the abdomen region (p < 0.05). Moreover, we showed intraepithelial apoptosis and proliferation of keratinocytes in the bulge of HF. In the study, Ki-67-positive and TUNEL-positive cell numbers were not statistically significant (p > 0.05). CONCLUSIONS: Our findings are important for further investigation of molecular aspects of the human hair follicle stem cells compartments in health and disease, which might be a promising model for comparative studies with different human diseases.

Impact of time from diagnosis to initiation of curative chemotherapy on survival of patients with diffuse large B-cell lymphoma.

Although it is generally regarded appropriate to start chemotherapy promptly after a diagnosis of diffuse large B-cell lymphoma (DLBCL), the optimal time from diagnosis to treatment (TDT) is unknown. A total of 689 patients diagnosed with DLBCL and treated with ≥ 1 cycle of CHOP-R with curative intent during 2003-2008 in British Columbia were identified: 347 (50%) TDT ≤ 4 weeks, 277 (40%) TDT 5-8 weeks, 65 (10%) TDT > 8 weeks. For the respective TDT groups, 5-year OS estimates were 61%, 74%, 63% (p = 0.006); 5-year PFS 57%, 70%, 61% (p = 0.006); and 5-year DSS 64%, 80%, 77% (p <0.001). In multivariate analysis, TDT >8 weeks was associated with worse OS (HR 1.20 (95% CI 1.03, 1.41), p = 0.020), PFS (HR 1.33 (95% CI 1.15, 1.54), p < 0.001), and DSS (HR 1.40 (95% CI 1.10, 1.78), p = 0.006). Clinicians should endeavor to initiate curative chemotherapy as soon as possible after a diagnosis of DLBCL is established.

Effect of place of residence and treatment on survival outcomes in patients with diffuse large B-cell lymphoma in British Columbia.

BACKGROUND: We examined the relationship between location of residence at the time of diagnosis of diffuse large B-cell lymphoma (DLBCL) and health outcomes in a geographically large Canadian province with publicly funded, universally available medical care. PATIENTS AND METHODS: The British Columbia Cancer Registry was used to identify all patients 18-80 years of age diagnosed with DLBCL between January 2003 and December 2008. Home and treatment center postal codes were used to determine urban versus rural status and driving distance to access treatment. RESULTS: We identified 1,357 patients. The median age was 64 years (range: 18-80 years), 59% were male, 50% were stage III/IV, 84% received chemotherapy with curative intent, and 32% received radiotherapy. There were 186 (14%) who resided in rural areas, 141 (10%) in small urban areas, 183 (14%) in medium urban areas, and 847 (62%) in large urban areas. Patient and treatment characteristics were similar regardless of location. Five-year overall survival (OS) was 62% for patients in rural areas, 44% in small urban areas, 53% in medium urban areas, and 60% in large urban areas (p = .018). In multivariate analysis, there was no difference in OS between rural and large urban area patients (hazard ratio [HR]: 1.0; 95% confidence interval [CI]: 0.7-1.4), although patients in small urban areas (HR: 1.4; 95% CI: 1.0-2.0) and medium urban areas (HR: 1.4; 95% CI: 1.0-1.9) had worse OS than those in large urban areas. CONCLUSION: Place of residence at diagnosis is associated with survival of patients with DLBCL in British Columbia, Canada. Rural patients have similar survival to those in large urban areas, whereas patients living in small and medium urban areas experience worse outcomes.

P-cadherin expression as a prognostic biomarker in a 3992 case tissue microarray series of breast cancer.

P-cadherin is a calcium-dependent cell-cell adhesion glycoprotein. P-cadherin expression is restricted to the myoepithelial cells in normal breast tissue, and aberrant staining has also been described in invasive tumors. Several small studies have reported P-cadherin as a marker of poor outcome in breast cancer patients but its prognostic significance in relation to other variables has not been established in a large series of breast cancers. A tissue microarray was constructed from 3992 cases of invasive breast carcinoma, and P-cadherin expression was evaluated using immunohistochemistry. Median follow-up was 12.5 years. The immunohistochemistry-based definitions of cancer subtypes were luminal (ER+ or PR+/HER2-), luminal/HER2+ (ER+ or PR+/HER2+), HER2+ (ER-/PR-/HER2+), and basal (ER-/PR-/HER2-/CK5/6+ or EGFR+). Clinical covariate and biomarker associations were assessed using contingency tables, and Pearson's χ(2) or Fisher's exact test. Survival associations were assessed using Kaplan-Meier plots, logrank and Breslow tests, and Cox proportional hazards regression analysis. P-cadherin was expressed in 34.8% (1290/3710, 50% cut point) of cases. P-cadherin staining was strongly associated with HER2+ and basal carcinoma subtypes (P<0.0005). P-cadherin-positive patients showed significantly poorer short-term (0-10 years) overall survival, disease-specific survival, distant relapse-free interval, and locoregional relapse-free interval in univariable models (P<0.05). In multivariable Cox models containing standard clinical covariates and cancer subtypes, P-cadherin did not show independent prognostic value. P-cadherin expression was positively associated with histological grade, chemotherapy, Ki-67, EGFR, CK5/6, p53, YB-1, and HER2 expression (P<0.002), and negatively associated with age at diagnosis, ER, PR, and Bcl-2 expression (P<0.0005). This study shows the value of P-cadherin as a marker of poor prognosis. The large sample size of this series clarifies contradictory findings of many smaller studies. P-cadherin positivity is associated with high-grade tumor subtypes and well-established markers of poor prognosis, and may represent a promising antibody therapeutic target.