Anti-proliferative and apoptotic effect of cannabinoids on human pancreatic ductal adenocarcinoma xenograft in BALB/c nude mice model.

Human pancreatic ductal adenocarcinoma (PDAC) is a highly malignant and lethal tumor of the exocrine pancreas. Cannabinoids extracted from the hemp plant Cannabis sativa have been suggested as a potential therapeutic agent in several human tumors. However, the anti-tumor effect of cannabinoids on human PDAC is not entirely clarified. In this study, the anti-proliferative and apoptotic effect of cannabinoid solution (THC:CBD at 1:6) at a dose of 1, 5, and 10 mg/kg body weight compared to the negative control (sesame oil) and positive control (5-fluorouracil) was investigated in human PDAC xenograft nude mice model. The findings showed that cannabinoids significantly decreased the mitotic cells and mitotic/apoptotic ratio, meanwhile dramatically increased the apoptotic cells. Parallelly, cannabinoids significantly downregulated Ki-67 and PCNA expression levels. Interestingly, cannabinoids upregulated BAX, BAX/BCL-2 ratio, and Caspase-3, meanwhile, downregulated BCL-2 expression level and could not change Caspase-8 expression level. These findings suggest that cannabinoid solution (THC:CBD at 1:6) could inhibit proliferation and induce apoptosis in human PDAC xenograft models. Cannabinoids, including THC:CBD, should be further studied for use as the potent PDCA therapeutic agent in humans.

Extracorporeal shock wave lithotripsy (ESWL) versus percutaneous nephrolithotomy (PCNL) or retrograde intrarenal surgery (RIRS) for kidney stones.

BACKGROUND: Nephrolithiasis is a common urological disease worldwide. Extracorporeal shock wave lithotripsy (ESWL) has been used for the treatment of renal stones since the 1980s, while retrograde intrarenal surgery (RIRS) and percutaneous nephrolithotomy (PCNL) are newer, more invasive treatment modalities that may have higher stone-free rates. The complications of RIRS and PCNL have decreased owing to improvement in surgical techniques and instruments. We re-evaluated the best evidence on this topic in an update of a Cochrane Review first published in 2014. OBJECTIVES: To assess the effects of extracorporeal shock wave lithotripsy compared with percutaneous nephrolithotomy or retrograde intrarenal surgery for treating kidney stones. SEARCH METHODS: We performed a comprehensive search in CENTRAL, MEDLINE, Embase, and ClinicalTrials.gov with no restrictions on language or publication status. The latest search date was 6 December 2022. SELECTION CRITERIA: We included randomized controlled trials (RCTs) and quasi-RCTs that compared ESWL with PCNL or RIRS for kidney stone treatment. DATA COLLECTION AND ANALYSIS: Two review authors independently classified studies, extracted data, and assessed risk of bias. Our primary outcomes were treatment success rate at three months (defined as residual fragments smaller than 4 mm, or as defined by the study authors), quality of life (QoL), and complications. Our secondary outcomes were retreatment rate, auxiliary procedures rate, and duration of hospital stay. We performed statistical analyses using a random-effects model and independently rated the certainty of evidence using the GRADE approach. MAIN RESULTS: We included 31 trials involving 3361 participants (3060 participants completed follow-up). Four trials were only available as an abstract. Overall mean age was 46.6 years and overall mean stone size was 13.4 mm. Most participants (93.8%) had kidney stones measuring 20 mm or less, and 68.9% had lower pole stones. ESWL versus PCNL ESWL may have a lower three-month treatment success rate than PCNL (risk ratio [RR] 0.67, 95% confidence interval [CI] 0.57 to 0.79; I2 = 87%; 12 studies, 1303 participants; low-certainty evidence). This corresponds to 304 fewer participants per 1000 (397 fewer to 194 fewer) reporting treatment success with ESWL. ESWL may have little or no effect on QoL after treatment compared with PCNL (1 study, 78 participants; low-certainty evidence). ESWL probably leads to fewer complications than PCNL (RR 0.62, 95% CI 0.47 to 0.82; I2 = 18%; 13 studies, 1385 participants; moderate-certainty evidence). This corresponds to 82 fewer participants per 1000 (115 fewer to 39 fewer) having complications after ESWL. ESWL versus RIRS ESWL may have a lower three-month treatment success rate than RIRS (RR 0.85, 95% CI 0.78 to 0.93; I2 = 63%; 13 studies, 1349 participants; low-certainty evidence). This corresponds to 127 fewer participants per 1000 (186 fewer to 59 fewer) reporting treatment success with ESWL. We are very uncertain about QoL after treatment; the evidence is based on three studies (214 participants) that we were unable to pool. We are very uncertain about the difference in complication rates between ESWL and RIRS (RR 0.93, 95% CI 0.63 to 1.36; I2 = 32%; 13 studies, 1305 participants; very low-certainty evidence). This corresponds to nine fewer participants per 1000 (49 fewer to 48 more) having complications after ESWL. AUTHORS' CONCLUSIONS: ESWL compared with PCNL may have lower three-month success rates, may have a similar effect on QoL, and probably leads to fewer complications. ESWL compared with RIRS may have lower three-month success rates, but the evidence on QoL outcomes and complication rates is very uncertain. These findings should provide valuable information to aid shared decision-making between clinicians and people with kidney stones who are undecided about these three options.

Gene Profiling of Cannabis-sativa-mediated Apoptosis in Human Melanoma Cells.

BACKGROUND/AIM: Malignant melanoma is an aggressive skin cancer, accounting for the majority of skin cancer deaths. Prognosis is often poor and finding effective treatment remains a challenge. Tetrahydrocannabinol (THC) and cannabidiol (CBD) are main bioactive components of Cannabis sativa plant extracts that have been shown to exert anti-tumor effects. In this study, we aimed to perform gene expression analysis of human melanoma A375 cells following stimulation with C. sativa extracts. MATERIALS AND METHODS: Gene expression profiles of A375 human melanoma and Vero (control) cell lines were evaluated by RNA sequencing and quantitative real-time PCR. RESULTS: Flow cytometry showed that the THC+CBD cannabis fractions induced apoptosis on A375 cells. Induction of apoptosis was accompanied by a notable up-regulation of DNA damage inducible transcript 3 (DDIT), nerve growth factor receptor (NGFR), colony-stimulating factor 2 (CSF2), growth arrest and DNA damage inducible beta (GADD45B), and thymic stromal lymphopoietin (TSLP) genes and down-regulation of aryl hydrocarbon receptor nuclear translocator 2 (ARNT2), cyclin E2 (CCNE2), integrin subunit alpha 9 (ITGA9), proliferating cell nuclear antigen (PCNA) and E2F transcription factor 1 (E2F1) genes. Treatment of A375 cells with the THC+CBD fraction inhibited the phosphorylation of ERK1/2 signaling pathway, which regulates melanoma cell proliferation. We showed that the THC+CBD combination disrupted melanoma cell migration. CONCLUSION: Use of C. sativa-derived extracts containing equal amounts of THC and CBD is proposed as a potential treatment of melanoma.

Antitumor Effects of Cannabinoids in Human Pancreatic Ductal Adenocarcinoma Cell Line (Capan-2)-Derived Xenograft Mouse Model.

Background: Pancreatic cancer is considered a rare type of cancer, but the mortality rate is high. Cannabinoids extracted from the cannabis plant have been interested as an alternative treatment in cancer patients. Only a few studies are available on the antitumor effects of cannabinoids in pancreatic cancer. Therefore, this study aims to evaluate the antitumor effects of cannabinoids in pancreatic cancer xenografted mouse model. Materials and Methods: Twenty-five nude mice were subcutaneously transplanted with a human pancreatic ductal adenocarcinoma cell line (Capan-2). All mice were randomly assigned into 5 groups including negative control (gavage with sesame oil), positive control (5 mg/kg 5-fluorouracil intraperitoneal administration), and cannabinoids groups that daily received THC:CBD, 1:6 at 1, 5, or 10 mg/kg body weight for 30 days, respectively. Xenograft tumors and internal organs were collected for histopathological examination and immunohistochemistry. Results: The average tumor volume was increased in all groups with no significant difference. The average apoptotic cells and caspase-3 positive cells were significantly increased in cannabinoid groups compared with the negative control group. The expression score of proliferating cell nuclear antigen in positive control and cannabinoids groups was decreased compared with the negative control group. Conclusions: Cannabinoids have an antitumor effect on the Capan-2-derived xenograft mouse model though induce apoptosis and inhibit proliferation of tumor cells in a dose-dependent manner.

Extracorporeal shock wave lithotripsy (ESWL) versus percutaneous nephrolithotomy (PCNL) or retrograde intrarenal surgery (RIRS) for kidney stones.

BACKGROUND: Stones in the urinary tract are a common medical problem in the general population. At present, the great expansion in minimally invasive techniques has led to the decrease in open surgery. Extracorporeal shock wave lithotripsy (ESWL) has been introduced as an alternative approach which disintegrates stones in the kidney and upper urinary tract through the use of shock waves. Nevertheless, as there are limitations with the success rate in ESWL, other minimally invasive modalities for kidney stones such as percutaneous nephrolithotomy (PCNL) and retrograde intrarenal surgery (RIRS) are also widely applied. This is an update of a review first published in 2009. OBJECTIVES: This review aimed to assess the effectiveness and complications of ESWL for kidney stones compared with PCNL or RIRS. SEARCH METHODS: We searched the Cochrane Renal Group's Specialised Register to 3 March 2014 through contact with the Trials' Search Co-ordinator using search terms relevant to this review. SELECTION CRITERIA: Randomised controlled trials (RCTs) assessing the use of ESWL compared to PCNL or RIRS for kidney stone management. DATA COLLECTION AND ANALYSIS: Two authors independently assessed all the studies for inclusion. Statistical analyses were performed using the random effects model and the results expressed as risk ratio (RR) for dichotomous outcomes or mean difference (MD) for continuous data with 95% confidence intervals (CI). MAIN RESULTS: Five studies (338 patients) were included, four studies compared ESWL to PCNL and one compared ESWL with RIRS. Random sequence generation was reported in three studies and unclear in two. Allocation concealment was not reported in any of the included studies. Blinding of participants and investigators could not be undertaken due to the nature of the interventions; blinding of outcome assessors was not reported. Reporting bias was judged to be low risk in all studies. One study was funded by industry and in one study the number of participants in each group was unbalanced.The success of treatment at three months was significantly greater in the PCNL compared to the ESWL group (3 studies, 201 participants: RR 0.46, 95% CI 0.35 to 0.62). Re-treatment (1 study, 122 participants: RR 1.81, 95% CI 0.66 to 4.99) and using auxiliary procedures (2 studies, 184 participants: RR 9.06, 95% CI 1.20 to 68.64) was significantly increased with ESWL group compared to PCNL. The efficiency quotient (EQ; used to assess the effectiveness of procedures) higher for PCNL than ESWL; however EQ decreased when stone size increased. Duration of treatment (MD -36.00 min, 95% CI -54.10 to -17.90) and hospital stay (1 study, 49 participants: MD -3.30 days, 95% CI -5.45 to -1.15) were significantly shorter in the ESWL group. Overall more complications were reported with PCNL, however we were unable to meta-analyse the included studies due to the differing outcomes reported and the timing of the outcome measurements.One study compared ESWL versus RIRS for lower pole kidney stones. The success of treatment was not significantly different at the end of the third month (58 participants: RR 0.91, 95% CI 0.64 to 1.30). Mean procedural time and mean hospital stay was reported to be longer in the RIRS group. AUTHORS' CONCLUSIONS: Results from five small studies, with low methodological quality, indicated ESWL is less effective for kidney stones than PCNL but not significantly different from RIRS. Hospital stay and duration of treatment was less with ESWL. Larger RCTs with high methodological quality are required to investigate the effectiveness and complications of ESWL for kidney stones compared to PCNL if there is any technological progress in the non-invasive elimination of the residual fragments. Moreover, further research is required for the outcomes of ESWL and RIRS in lower and non-lower pole studies including PCNL versus RIRS.

Extracorporeal shock wave lithotripsy (ESWL) versus percutaneous nephrolithotomy (PCNL) or retrograde intrarenal surgery (RIRS) for kidney stones.

BACKGROUND: Stones in the urinary tract are a common medical problem in the general population. At present, the great expansion in minimally invasive techniques has led to the decrease in open surgery. Extracorporeal shock wave lithotripsy (ESWL) has been introduced as an alternative approach which disintegrates stones in the kidney and upper urinary tract through the use of shock waves. Nevertheless, as there are limitations with the success rate in ESWL, other minimally invasive modalities for kidney stones such as percutaneous nephrolithotomy (PCNL) and retrograde intrarenal surgery (RIRS) are also widely applied. OBJECTIVES: To evaluate the effectiveness and complications of ESWL compared with PCNL or RIRS for managing kidney stones. SEARCH STRATEGY: We searched the Cochrane Central Register of Controlled Trials (CENTRAL in The Cochrane Library), MEDLINE, EMBASE and reference lists of articles without language restriction. SELECTION CRITERIA: Randomised controlled trials (RCTs) assessing the use of ESWL compared to PCNL or RIRS for kidney stone management. DATA COLLECTION AND ANALYSIS: Two authors independently assessed all the studies for inclusion. Statistical analyses were performed using the random effects model and the results expressed as risk ratio (RR) for dichotomous outcomes or mean difference (MD) for continuous data with 95% confidence intervals (CI). MAIN RESULTS: Three studies (214 patients) were included, however results could not be pooled. Two RCTs compared ESWL to PCNL. The success rate at three months for lower pole kidney stones was statistically higher for PCNL (RR 0.39, 95% CI 0.27 to 0.56). Re-treatment (RR 1.81, 95% CI 0.66 to 4.99) and using auxiliary procedures (RR 9.06, 95% CI 1.20 to 68.64) after PCNL were less compared to ESWL. The efficiency quotient (EQ) in PCNL was higher than ESWL. Hospital stay (MD -3.30 days, 95% CI -5.45 to -1.15), duration of treatment (MD -36.00 minutes, 95% CI -54.10 to -17.90) and complications were less for ESWL. One RCT compared ESWL versus RIRS for lower pole kidney stones. The success rate was not significantly different at the end of the third month (RR 0.91, 95% CI 0.64 to 1.30). AUTHORS' CONCLUSIONS: Results from three small studies, with low methodological quality, indicated ESWL is less effective for lower pole kidney stones than PCNL but not significantly different from RIRS. Hospital stay and duration of treatment was less with ESWL. More RCTs are required to investigate the effectiveness and complications of ESWL for kidney stones compared to PCNL or RIRS.