Pub Date : 2019-01-20DOI: 10.31083/j.jmcm.2019.01.9231
Malshy Kamil, Nativ Omri, Sadeh Omer, A. Tareq, Kastin Alexander, K. Alexander, E. Gilad, Mullerad Michael, Hoffman Azik
Purpose: Fever occurring post transurethral resection of prostate (TURP) due to urinary tract infection (UTI) is a wellknown complication. A better knowledge of pre-operative risk factors will aid the prevention and treatment of this complication. Herein we aimed to describe the risk factors for postoperative fever in a cohort of patients undergoing TURP in a single institute. Methods: A total of 177 patients underwent transurethral resection of prostate (TURP) between January 2016 and August 2017 in our Institute. Postoperative fever was defined as ≥ 38 ◦C up to a week after surgery. Other reasons for post-operative fever were excluded. We collected data for indwelling catheter, antibiotic prophylactic treatment, positive preoperative urine culture, diabetes mellitus (DM), combined cystolithotripsy and prostate size. Results: All patients received antibiotic prophylaxis prior to the TURP procedure. Patients with negative urine culture were treated with IV Amikacin + Ampicillin (n = 83), whereas patients with positive bacterial cultures were treated as per antibiotic sensitivity profile (n = 93). One patient developed fever in the negative culture group, compared to 8 in the positive urine culture group (P = 0.0375). No patient developed septic shock. Smaller prostate size (RR = 1.06, CI-95%, 1.01-1.12, P = 0.016), positive urine culture (RR = 3.85, CI-95%, 1.33-100, P = 0.033) and older age (RR = 1.1, CI-95%, 1.01-1.21, P= 0.031) were all predictors of postoperative fever. In contrast, TURP combined with cystolithotripsy (P = 0.99), indwelling urethral catheter (P = 0.155), and patients with DM (P = 0.256) were not predictors of postoperative fever. Conclusions: Positive urinary bacterial culture prior to TURP is a frequent event. Although positive urinary culture increased the risk of post TURP fever, none of these events caused significant morbidity. Surprisingly, a smaller prostate size increased the risk of postoperative fever. This fact suggests that the degree of infection is attributed to the level of obstruction and not to the volume of the prostate.
{"title":"Risk factors predicting fever following trans-urethral prostatectomy","authors":"Malshy Kamil, Nativ Omri, Sadeh Omer, A. Tareq, Kastin Alexander, K. Alexander, E. Gilad, Mullerad Michael, Hoffman Azik","doi":"10.31083/j.jmcm.2019.01.9231","DOIUrl":"https://doi.org/10.31083/j.jmcm.2019.01.9231","url":null,"abstract":"Purpose: Fever occurring post transurethral resection of prostate (TURP) due to urinary tract infection (UTI) is a wellknown complication. A better knowledge of pre-operative risk factors will aid the prevention and treatment of this complication. Herein we aimed to describe the risk factors for postoperative fever in a cohort of patients undergoing TURP in a single institute. Methods: A total of 177 patients underwent transurethral resection of prostate (TURP) between January 2016 and August 2017 in our Institute. Postoperative fever was defined as ≥ 38 ◦C up to a week after surgery. Other reasons for post-operative fever were excluded. We collected data for indwelling catheter, antibiotic prophylactic treatment, positive preoperative urine culture, diabetes mellitus (DM), combined cystolithotripsy and prostate size. Results: All patients received antibiotic prophylaxis prior to the TURP procedure. Patients with negative urine culture were treated with IV Amikacin + Ampicillin (n = 83), whereas patients with positive bacterial cultures were treated as per antibiotic sensitivity profile (n = 93). One patient developed fever in the negative culture group, compared to 8 in the positive urine culture group (P = 0.0375). No patient developed septic shock. Smaller prostate size (RR = 1.06, CI-95%, 1.01-1.12, P = 0.016), positive urine culture (RR = 3.85, CI-95%, 1.33-100, P = 0.033) and older age (RR = 1.1, CI-95%, 1.01-1.21, P= 0.031) were all predictors of postoperative fever. In contrast, TURP combined with cystolithotripsy (P = 0.99), indwelling urethral catheter (P = 0.155), and patients with DM (P = 0.256) were not predictors of postoperative fever. Conclusions: Positive urinary bacterial culture prior to TURP is a frequent event. Although positive urinary culture increased the risk of post TURP fever, none of these events caused significant morbidity. Surprisingly, a smaller prostate size increased the risk of postoperative fever. This fact suggests that the degree of infection is attributed to the level of obstruction and not to the volume of the prostate.","PeriodicalId":92248,"journal":{"name":"Journal of molecular medicine and clinical applications","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2019-01-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"81466823","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2018-12-20DOI: 10.31083/j.jmcm.2018.04.407
Nativ Omri, Dalal Eilata, S. Edmond, Aronson Moshe, H. Guy, Nativ Ofer
Background: Non-muscle invasive form (NMIBC) is a chronic disease with a high recurrence rate and requires lifelong surveillance. Various intravesical agents were shown to reduce tumor recurrence but unfortunately, none of these agents proved to be of benefit in long-term prevention of local recurrence or disease progression. Aim of Research: Previous studies have shown that Halofuginone (HF), an antiprotozoal agent, exerts anti-neoplastic activity in various cancer models. Our aim was to evaluate the in vivo activity of oral and intravesical HF treatment in an experimental mouse model harboring NMIBC. Methods: Initially, 60 mice were divided into six treatment groups to evaluate the toxicity of this anti-parasitic agent on the bladder mucosa. The second stage included 126 mice which underwent intravesical implantation with Mouse Bladder Tumor cells (MBT-2): Group 1 (n = 30) received no treatment, group 2 (n = 32) received 6 intravesical instillations of PBS, group 3 (n = 32) received 6 doses of 250 μg oral HF, whereas group 4 (n = 32) received 6 intravesical instillations of 250 μg HF. Results: The average weight of bladders, which reflects the anti-neoplastic activity, differed significantly between the control and treated groups: 88.8 mg ± 15.58 SEM and 81.2 mg ± 13.79 SEM for untreated and PBS-treated mice, respectively, versus 38.0 mg ± 4.02 SEM and 39.6 mg ± 5.97 SEM for animals treated with oral and intravesical HF, respectively. Conclusions: HF exerted a significant anti-neoplastic activity in mice bearing NMIBC upon oral as well as intravesical administration. These results may constitute the basis for the maintenance of oral treatment with HF in patients with NMIBC. Submitted: November 12, 2018; Revised: November 24, 2018; Accepted: November 25, 2018
{"title":"Halofuginone: a novel oral and intravesical agent for the treatment of non-muscle invasive bladder cancer","authors":"Nativ Omri, Dalal Eilata, S. Edmond, Aronson Moshe, H. Guy, Nativ Ofer","doi":"10.31083/j.jmcm.2018.04.407","DOIUrl":"https://doi.org/10.31083/j.jmcm.2018.04.407","url":null,"abstract":"Background: Non-muscle invasive form (NMIBC) is a chronic disease with a high recurrence rate and requires lifelong surveillance. Various intravesical agents were shown to reduce tumor recurrence but unfortunately, none of these agents proved to be of benefit in long-term prevention of local recurrence or disease progression. Aim of Research: Previous studies have shown that Halofuginone (HF), an antiprotozoal agent, exerts anti-neoplastic activity in various cancer models. Our aim was to evaluate the in vivo activity of oral and intravesical HF treatment in an experimental mouse model harboring NMIBC. Methods: Initially, 60 mice were divided into six treatment groups to evaluate the toxicity of this anti-parasitic agent on the bladder mucosa. The second stage included 126 mice which underwent intravesical implantation with Mouse Bladder Tumor cells (MBT-2): Group 1 (n = 30) received no treatment, group 2 (n = 32) received 6 intravesical instillations of PBS, group 3 (n = 32) received 6 doses of 250 μg oral HF, whereas group 4 (n = 32) received 6 intravesical instillations of 250 μg HF. Results: The average weight of bladders, which reflects the anti-neoplastic activity, differed significantly between the control and treated groups: 88.8 mg ± 15.58 SEM and 81.2 mg ± 13.79 SEM for untreated and PBS-treated mice, respectively, versus 38.0 mg ± 4.02 SEM and 39.6 mg ± 5.97 SEM for animals treated with oral and intravesical HF, respectively. Conclusions: HF exerted a significant anti-neoplastic activity in mice bearing NMIBC upon oral as well as intravesical administration. These results may constitute the basis for the maintenance of oral treatment with HF in patients with NMIBC. Submitted: November 12, 2018; Revised: November 24, 2018; Accepted: November 25, 2018","PeriodicalId":92248,"journal":{"name":"Journal of molecular medicine and clinical applications","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2018-12-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"87495906","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2018-12-20DOI: 10.31083/J.JMCM.2018.04.403
Corno Cristina, P. Paola
Platinum compounds are widely used antitumor agents known to interfere with DNA function by forming DNA crosslinks and DNA-protein crosslinks. Because of their electrophilicity, platinum compounds can interact with nucleophilic residues of all macromolecules. Consequently, this cross-linking inhibits DNA replication in cancer cells. Immunogenic and immunomodulating effects have been ascribed to platinum drugs, with differences and similarities among cisplatin, carboplatin and oxaliplatin. On the one hand, cisplatin is generally unable to induce immunogenic cell death; on the other hand, oxaliplatin appears to be a good inducer, thanks to its capability to efficiently trigger calreticulin exposure to the tumor cell plasma membrane. Conversely, cisplatin, carboplatin and oxaliplatin can relieve immunosuppressive networks e.g., by decreasing PDL-1 and PDL-2 in dendritic and tumor cells. Such drugs are also capable of modulating MHC molecules via IFN-β production and T-cell mediated lysis. The concentrations appear to be key in determining the immunomodulatory properties of these cytotoxic agents, with low in vivo doses usually playing stimulatory effects. As predicted from preclinical models, supportive results have emerged from clinical studies, particularly those based on chemotherapeutic regimens of platinum compounds combined with immunotherapeutics. Future therapeutic interventions are expected to benefit from a better definition of the molecular effects of platinum compounds on the immune system.
{"title":"Novel aspects of the preclinical pharmacology of platinum compounds","authors":"Corno Cristina, P. Paola","doi":"10.31083/J.JMCM.2018.04.403","DOIUrl":"https://doi.org/10.31083/J.JMCM.2018.04.403","url":null,"abstract":"Platinum compounds are widely used antitumor agents known to interfere with DNA function by forming DNA crosslinks and DNA-protein crosslinks. Because of their electrophilicity, platinum compounds can interact with nucleophilic residues of all macromolecules. Consequently, this cross-linking inhibits DNA replication in cancer cells. Immunogenic and immunomodulating effects have been ascribed to platinum drugs, with differences and similarities among cisplatin, carboplatin and oxaliplatin. On the one hand, cisplatin is generally unable to induce immunogenic cell death; on the other hand, oxaliplatin appears to be a good inducer, thanks to its capability to efficiently trigger calreticulin exposure to the tumor cell plasma membrane. Conversely, cisplatin, carboplatin and oxaliplatin can relieve immunosuppressive networks e.g., by decreasing PDL-1 and PDL-2 in dendritic and tumor cells. Such drugs are also capable of modulating MHC molecules via IFN-β production and T-cell mediated lysis. The concentrations appear to be key in determining the immunomodulatory properties of these cytotoxic agents, with low in vivo doses usually playing stimulatory effects. As predicted from preclinical models, supportive results have emerged from clinical studies, particularly those based on chemotherapeutic regimens of platinum compounds combined with immunotherapeutics. Future therapeutic interventions are expected to benefit from a better definition of the molecular effects of platinum compounds on the immune system.","PeriodicalId":92248,"journal":{"name":"Journal of molecular medicine and clinical applications","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2018-12-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"78506797","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2018-12-20DOI: 10.31083/J.JMCM.2018.04.4221
C. Maria, A. Marianne, U. K. Abdul, K. Asli, van Wieringen Wessel, A. Bart
Neuroblastoma is a pediatric tumor that originates from cells of the adrenergic lineage. Here we investigated the balance between differentiation and dedifferentiation in relation to tumor-engraftment potential in preclinical mouse models. We analyzed intratumoral heterogeneity through comparison of marker expression of normal adrenergic development versus tumor marker expression, which showed the presence of sympathoadrenal as well as mesenchymal subtypes of neuroblastomas cells. Subsequently, we evaluated long-term outgrowth capacity of these two (FACS-sorted) cell populations, which showed that adrenergic cells have a stronger long-term clonogenic potential. Engraftment of these sorted populations into mice revealed the occurrence of heterogeneous populations. Modelling of the interconversion rate indicated that cell fate transitions from the adrenergic to mesenchymal state were obtained gradually and stochastically as the tumors grew in mice. We found that adrenergic cells have an increased tumorigenic potential in mice without signs of beneficial cross talk between the two lineage populations. These findings indicate that neuroblastoma contains two rivalling differentiation states that exhibit differences in long term clonal/tumorigenic potential. We expect these states to be relevant for therapy resistance as a result of intratumoral heterogeneity. Submitted: November 22, 2018; Revised: December 9, 2018; Accepted: December 15, 2018
{"title":"Adrenergic to mesenchymal fate switching of neuroblastoma occurs spontaneously in vivo resulting in differential tumorigenic potential","authors":"C. Maria, A. Marianne, U. K. Abdul, K. Asli, van Wieringen Wessel, A. Bart","doi":"10.31083/J.JMCM.2018.04.4221","DOIUrl":"https://doi.org/10.31083/J.JMCM.2018.04.4221","url":null,"abstract":"Neuroblastoma is a pediatric tumor that originates from cells of the adrenergic lineage. Here we investigated the balance between differentiation and dedifferentiation in relation to tumor-engraftment potential in preclinical mouse models. We analyzed intratumoral heterogeneity through comparison of marker expression of normal adrenergic development versus tumor marker expression, which showed the presence of sympathoadrenal as well as mesenchymal subtypes of neuroblastomas cells. Subsequently, we evaluated long-term outgrowth capacity of these two (FACS-sorted) cell populations, which showed that adrenergic cells have a stronger long-term clonogenic potential. Engraftment of these sorted populations into mice revealed the occurrence of heterogeneous populations. Modelling of the interconversion rate indicated that cell fate transitions from the adrenergic to mesenchymal state were obtained gradually and stochastically as the tumors grew in mice. We found that adrenergic cells have an increased tumorigenic potential in mice without signs of beneficial cross talk between the two lineage populations. These findings indicate that neuroblastoma contains two rivalling differentiation states that exhibit differences in long term clonal/tumorigenic potential. We expect these states to be relevant for therapy resistance as a result of intratumoral heterogeneity. Submitted: November 22, 2018; Revised: December 9, 2018; Accepted: December 15, 2018","PeriodicalId":92248,"journal":{"name":"Journal of molecular medicine and clinical applications","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2018-12-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"82116085","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2018-12-20DOI: 10.31083/j.jmcm.2018.04.401
Adrián Puerta, A. Galán, Miguel X. Fernandes, José M. Padrón
In the scenario of drug discovery, the challenge is to fully understand and elucidate the mechanism of action to identify, with high resolution, the molecular determinant(s) targeted by the drug and responsible for its pharmacological activity. Cancer offers scientists an almost infinite arena of signaling pathways, targets and small molecules for therapeutic intervention. Among the multiple chemotherapeutic strategies to combat cancer, synthetic lethality remains underexplored. Casein kinase 1 ε (CK1ε) is a serine/threonine protein kinase that has been described as a synthetic lethal partner of the Wnt/β -catenin signaling pathway. Despite its potential as a desirable therapeutic target, only two selective inhibitors are available: PF-4800567 and GSD0054. Until the discovery of GSD0054, CK1ε inhibitors have been considered candidate drugs exclusively in psychopharmacology. In this review, we focus on three key points which we consider essential to define the scope of CK1ε as a synthetic lethal partner and its inhibitors as chemotherapeutics: the therapeutic relevance of this kinase, the scarce availability of selective inhibitors (due to the high homology with its sibling isoform CK1δ ), and the constraint of existing computational tools. This paper represents the first review covering the potential of CK1ε as a druggable target for cancer treatment.
{"title":"Facts and myths of selective casein kinase 1ε einhibition","authors":"Adrián Puerta, A. Galán, Miguel X. Fernandes, José M. Padrón","doi":"10.31083/j.jmcm.2018.04.401","DOIUrl":"https://doi.org/10.31083/j.jmcm.2018.04.401","url":null,"abstract":"In the scenario of drug discovery, the challenge is to fully understand and elucidate the mechanism of action to identify, with high resolution, the molecular determinant(s) targeted by the drug and responsible for its pharmacological activity. Cancer offers scientists an almost infinite arena of signaling pathways, targets and small molecules for therapeutic intervention. Among the multiple chemotherapeutic strategies to combat cancer, synthetic lethality remains underexplored. Casein kinase 1 ε (CK1ε) is a serine/threonine protein kinase that has been described as a synthetic lethal partner of the Wnt/β -catenin signaling pathway. Despite its potential as a desirable therapeutic target, only two selective inhibitors are available: PF-4800567 and GSD0054. Until the discovery of GSD0054, CK1ε inhibitors have been considered candidate drugs exclusively in psychopharmacology. In this review, we focus on three key points which we consider essential to define the scope of CK1ε as a synthetic lethal partner and its inhibitors as chemotherapeutics: the therapeutic relevance of this kinase, the scarce availability of selective inhibitors (due to the high homology with its sibling isoform CK1δ ), and the constraint of existing computational tools. This paper represents the first review covering the potential of CK1ε as a druggable target for cancer treatment.","PeriodicalId":92248,"journal":{"name":"Journal of molecular medicine and clinical applications","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2018-12-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"87269183","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2018-12-20DOI: 10.31083/j.jmcm.2018.04.405
Gutmacher Zvi, Blumenfeld Israel, Elimelech Rina
A single traumatic injury to the head, neck and temporomandibular joint that occurs during a sudden motor vehicle collision, is known as whiplash. In spite of the fact that whiplash injury is undefined and does not reflect the biomechanical events of motor vehicle accidents, temporomandibular symptoms may be associated with or occur independently of whiplash-associated disorders. The purpose of this review is to clarify whether a true correlation between temporomandibular joint (TMJ) dysfunction and whiplash injury exists. To this aim, a PubMed/Medline search was conducted using the terms “temporomandibular dysfunction”, “jaw pain”, “temporomandibular joint”, “whiplash”, “motor-vehicle accidents” and “motor-vehicle collisions”. Over 200 related articles were reviewed. The incidence of TMJ dysfunction resulting from whiplash varies from low to moderate and the mechanism of injury is poorly understood. Oral health care providers should be aware of the possible influence of litigation following motor vehicle accidents and its association with the so-called late whiplash syndrome. To date, there is no direct correlation between whiplash injury and TMJ dysfunction. The effect of whiplash on TMJ function is limited in terms of duration and often disappears without complications. A systematic and careful approach is needed when treating TMJ symptoms after whiplash and a differential diagnosis should be considered when temporomandibular joint disorder manifestations occur long after the whiplash incidence.
{"title":"The whiplash injury phenomenon: a review of the literature","authors":"Gutmacher Zvi, Blumenfeld Israel, Elimelech Rina","doi":"10.31083/j.jmcm.2018.04.405","DOIUrl":"https://doi.org/10.31083/j.jmcm.2018.04.405","url":null,"abstract":"A single traumatic injury to the head, neck and temporomandibular joint that occurs during a sudden motor vehicle collision, is known as whiplash. In spite of the fact that whiplash injury is undefined and does not reflect the biomechanical events of motor vehicle accidents, temporomandibular symptoms may be associated with or occur independently of whiplash-associated disorders. The purpose of this review is to clarify whether a true correlation between temporomandibular joint (TMJ) dysfunction and whiplash injury exists. To this aim, a PubMed/Medline search was conducted using the terms “temporomandibular dysfunction”, “jaw pain”, “temporomandibular joint”, “whiplash”, “motor-vehicle accidents” and “motor-vehicle collisions”. Over 200 related articles were reviewed. The incidence of TMJ dysfunction resulting from whiplash varies from low to moderate and the mechanism of injury is poorly understood. Oral health care providers should be aware of the possible influence of litigation following motor vehicle accidents and its association with the so-called late whiplash syndrome. To date, there is no direct correlation between whiplash injury and TMJ dysfunction. The effect of whiplash on TMJ function is limited in terms of duration and often disappears without complications. A systematic and careful approach is needed when treating TMJ symptoms after whiplash and a differential diagnosis should be considered when temporomandibular joint disorder manifestations occur long after the whiplash incidence.","PeriodicalId":92248,"journal":{"name":"Journal of molecular medicine and clinical applications","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2018-12-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"78926330","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2018-12-20DOI: 10.31083/j.jmcm.2018.04.402
Shaylovsky Ghersin Dana, G. Itamar, M. Boaz, Nativ Ofer, Halachmi Sarel
Background and aim: Microscopic hematuria (MH) is a common finding in urinalysis, existing in up to 30% of evaluated patients. Due to the relatively high rate of malignancy reported in patients with MH, a full urologi-cal evaluation to detect urothelial cancer is advocated by the American Urological Association (AUA) and the European Association of Urology (EAU) in woman with asymptomatic microhema-turia, once infection or urolithiasis were rule out. In contrast to the strict guidelines, our personal experience shows a very low rate of malignancies in women with asymptomatic microhematuria. Hence, the aim of our current study was to assess the rate of urothelial malignancies found during evaluation of asymptomatic women with recurrent MH in a pilot study. Methods: In the current retrospective study we retrieved the records of all women with asymptomatic MH who underwent an elective cystoscopy in our outpatient clinic during the years 2010-2015. We ex-amined the impact of their age, smoking status, upper tract imaging (sonography or CT-Urography), urine cytology results on cystoscopy results and pathological outcome. Results: 165 consecutive patients were included in the study: 1 had abnormal imaging, 2 women had abnor-mal urine cytology (atypia), and 2 had abnormal cystoscopy; 5 women were younger than 35, and all had a completely normal workup. None of the patients were diagnosed with urothelial cancer. Conclusions: A full urological investigation had a low yield in our cohort of women with asymptomatic microhe-maturia, and therefore may be unnecessary, especially in younger women.
{"title":"Urothelial cancer rate in women with asymptomatic microhematuria. Is there a justification for full hematuria evaluation?","authors":"Shaylovsky Ghersin Dana, G. Itamar, M. Boaz, Nativ Ofer, Halachmi Sarel","doi":"10.31083/j.jmcm.2018.04.402","DOIUrl":"https://doi.org/10.31083/j.jmcm.2018.04.402","url":null,"abstract":"Background and aim: Microscopic hematuria (MH) is a common finding in urinalysis, existing in up to 30% of evaluated patients. Due to the relatively high rate of malignancy reported in patients with MH, a full urologi-cal evaluation to detect urothelial cancer is advocated by the American Urological Association (AUA) and the European Association of Urology (EAU) in woman with asymptomatic microhema-turia, once infection or urolithiasis were rule out. In contrast to the strict guidelines, our personal experience shows a very low rate of malignancies in women with asymptomatic microhematuria. Hence, the aim of our current study was to assess the rate of urothelial malignancies found during evaluation of asymptomatic women with recurrent MH in a pilot study. Methods: In the current retrospective study we retrieved the records of all women with asymptomatic MH who underwent an elective cystoscopy in our outpatient clinic during the years 2010-2015. We ex-amined the impact of their age, smoking status, upper tract imaging (sonography or CT-Urography), urine cytology results on cystoscopy results and pathological outcome. Results: 165 consecutive patients were included in the study: 1 had abnormal imaging, 2 women had abnor-mal urine cytology (atypia), and 2 had abnormal cystoscopy; 5 women were younger than 35, and all had a completely normal workup. None of the patients were diagnosed with urothelial cancer. Conclusions: A full urological investigation had a low yield in our cohort of women with asymptomatic microhe-maturia, and therefore may be unnecessary, especially in younger women.","PeriodicalId":92248,"journal":{"name":"Journal of molecular medicine and clinical applications","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2018-12-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"72513609","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2018-12-20DOI: 10.31083/J.JMCM.2018.04.325001
Gazzano Elena, Kopecka Joanna, C. Barbara, Buondonno Ilaria, C. Costanzo, R. Chiara
Doxorubicin (dox) is one of the first-line drug treatment in osteosarcoma. P-glycoprotein (Pgp) limits dox’s intracellular accumulation and efficacy in osteosarcoma. Part of the cytotoxic effects of dox are mediated by the induction of immunogenic cell death (ICD) that allows a durable eradication of the tumor by the host immune system. Pgp-overexpressing tumors, however, are also ICD-resistant. We recently synthesized two classes of synthetic doxs – nitric oxide (NO)-releasing dox and H2S-releasing dox – that were cytotoxic against different Pgp-expressing tumors. The aim of this work is to investigate if the lead compounds (termed Ndox and Sdox) were able to elicit ICD in Pgp-positive/dox-resistant osteosarcoma cells. Ndox and Sdox induced apoptosis in both sensitive and resistant cells, were localized within the endolasmic reticulum (ER), up-regulated ER stress-dependent cell death genes, promoted the translocation of calreticulin form ER to cell surface, induced the extracellular release of ATP and HMGB1, increased the phagocytosis of tumor cells by dendritic cells and the expansion of anti-tumor CD8+T-lymphocytes, in a NOand H2S-dependent manner, respectively. Expanded CD8+clones up-regulated immune-activating cytokines and down-regulated immune-suppressive cytokines. Dox induced the same events in sensitive cells, but not in Pgp-expressing/doxresistant cells. We suggest Ndox and Sdox as new multifunctional anthracyclines able to induce apoptosis of resistant osteosarcoma cells and contemporarily activate an anti-tumor immune response. These pro-drugs may have a future use in osteosarcoma patients with high Pgp expression, characterized by a poor outcome because of the lack of durable tumor eradication and the high frequency of relapse.
{"title":"Novel anthracyclines with enhanced immunogenic effects against drug resistant osteosarcoma cells","authors":"Gazzano Elena, Kopecka Joanna, C. Barbara, Buondonno Ilaria, C. Costanzo, R. Chiara","doi":"10.31083/J.JMCM.2018.04.325001","DOIUrl":"https://doi.org/10.31083/J.JMCM.2018.04.325001","url":null,"abstract":"Doxorubicin (dox) is one of the first-line drug treatment in osteosarcoma. P-glycoprotein (Pgp) limits dox’s intracellular accumulation and efficacy in osteosarcoma. Part of the cytotoxic effects of dox are mediated by the induction of immunogenic cell death (ICD) that allows a durable eradication of the tumor by the host immune system. Pgp-overexpressing tumors, however, are also ICD-resistant. We recently synthesized two classes of synthetic doxs – nitric oxide (NO)-releasing dox and H2S-releasing dox – that were cytotoxic against different Pgp-expressing tumors. The aim of this work is to investigate if the lead compounds (termed Ndox and Sdox) were able to elicit ICD in Pgp-positive/dox-resistant osteosarcoma cells. Ndox and Sdox induced apoptosis in both sensitive and resistant cells, were localized within the endolasmic reticulum (ER), up-regulated ER stress-dependent cell death genes, promoted the translocation of calreticulin form ER to cell surface, induced the extracellular release of ATP and HMGB1, increased the phagocytosis of tumor cells by dendritic cells and the expansion of anti-tumor CD8+T-lymphocytes, in a NOand H2S-dependent manner, respectively. Expanded CD8+clones up-regulated immune-activating cytokines and down-regulated immune-suppressive cytokines. Dox induced the same events in sensitive cells, but not in Pgp-expressing/doxresistant cells. We suggest Ndox and Sdox as new multifunctional anthracyclines able to induce apoptosis of resistant osteosarcoma cells and contemporarily activate an anti-tumor immune response. These pro-drugs may have a future use in osteosarcoma patients with high Pgp expression, characterized by a poor outcome because of the lack of durable tumor eradication and the high frequency of relapse.","PeriodicalId":92248,"journal":{"name":"Journal of molecular medicine and clinical applications","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2018-12-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"83595133","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2018-12-20DOI: 10.31083/j.jmcm.2018.04.502
Azucena Marset-Castro, Álvaro López-Gallardo, H. López-Muñoz, L. Sánchez-Sánchez, Inés Maya, Ó. López, J. Fernández-Bolaños
We report an efficient synthesis of phenolic peptides starting from 3,4-dihydroxyphenylacetic acid (DOPAC) and L-configured amino acid esters (glycine, phenylalanine, valine, serine, tryptophan, and cystine) using different coupling reagents. The combination of a phenolic scaffold with an amino acid residue might modulate the bioavailability and the therapeutic properties of title derivatives. Moreover, the incorporation of a catechol group, with inherent redox activity, can contribute to alter the redox status of the cancer cells, and therefore, provide anti-proliferative properties. Their activities as antioxidants (i.e. scavenging free radicals and H2O2 as well inhibition of lipid peroxidation) and as anti-proliferative agents against three human cervical carcinoma cell lines (HeLa, ViBo, and CaSki) and normal lymphocytes were evaluated. All compounds exhibited an excellent antioxidant activity; remarkably, the peptide derived from L-cystine exhibited the best antioxidant activity, displaying a 2.5-fold increase in radical-scavenging activity when compared with the natural 2-(3’,4’-dihydroxyphenyl)ethanol (hydroxytyrosol, HT). Moreover, this compound was also the most potent antitumor agent against the three human tumor cell lines (IC50 values 108-122 μM), with a 2-7-fold increase in activity when compared with natural DOPAC and HT, used as reference compounds. Importantly, the cytotoxic activity of these phenolic peptidomimetics against normal human lymphocytes was very low, hence confirming their selectivity towards tumor cells. Moreover, a disulfide-containing peptide also exhibited negligible cell necrosis and a high selectivity against tumor cells when compared to normal lymphocytes. Such derivative incorporates two fragments characterized with redox properties, the catechol moiety, and the disulfide linker. Thus, disulfide-containing phenolic peptidomimetics emerge as good lead candidates for the development of a novel family of anti-tumor agents.
{"title":"Phenolic peptides as antioxidant and anti-proliferative agents","authors":"Azucena Marset-Castro, Álvaro López-Gallardo, H. López-Muñoz, L. Sánchez-Sánchez, Inés Maya, Ó. López, J. Fernández-Bolaños","doi":"10.31083/j.jmcm.2018.04.502","DOIUrl":"https://doi.org/10.31083/j.jmcm.2018.04.502","url":null,"abstract":"We report an efficient synthesis of phenolic peptides starting from 3,4-dihydroxyphenylacetic acid (DOPAC) and L-configured amino acid esters (glycine, phenylalanine, valine, serine, tryptophan, and cystine) using different coupling reagents. The combination of a phenolic scaffold with an amino acid residue might modulate the bioavailability and the therapeutic properties of title derivatives. Moreover, the incorporation of a catechol group, with inherent redox activity, can contribute to alter the redox status of the cancer cells, and therefore, provide anti-proliferative properties. Their activities as antioxidants (i.e. scavenging free radicals and H2O2 as well inhibition of lipid peroxidation) and as anti-proliferative agents against three human cervical carcinoma cell lines (HeLa, ViBo, and CaSki) and normal lymphocytes were evaluated. All compounds exhibited an excellent antioxidant activity; remarkably, the peptide derived from L-cystine exhibited the best antioxidant activity, displaying a 2.5-fold increase in radical-scavenging activity when compared with the natural 2-(3’,4’-dihydroxyphenyl)ethanol (hydroxytyrosol, HT). Moreover, this compound was also the most potent antitumor agent against the three human tumor cell lines (IC50 values 108-122 μM), with a 2-7-fold increase in activity when compared with natural DOPAC and HT, used as reference compounds. Importantly, the cytotoxic activity of these phenolic peptidomimetics against normal human lymphocytes was very low, hence confirming their selectivity towards tumor cells. Moreover, a disulfide-containing peptide also exhibited negligible cell necrosis and a high selectivity against tumor cells when compared to normal lymphocytes. Such derivative incorporates two fragments characterized with redox properties, the catechol moiety, and the disulfide linker. Thus, disulfide-containing phenolic peptidomimetics emerge as good lead candidates for the development of a novel family of anti-tumor agents.","PeriodicalId":92248,"journal":{"name":"Journal of molecular medicine and clinical applications","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2018-12-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"89881202","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2018-09-20DOI: 10.31083/J.JMCM.2018.03.007
Kolluru D. Srikanth, T. Meirson, D. S. Sams, H. Gil-Henn
Brain disorders are now identified as one of the largest and costliest health risks throughout human life. While most brain disorders are not life threatening per se, their chronic and incurable nature renders the overall burden from these disorders much greater than would be suggested by mortality figures alone. Several neurodevelopmental conditions, including autism and dyslexia, are being diagnosed at increasing rates throughout the last few decades. Adolescence is now well recognized as a vulnerable brain developmental phase, in which mental disorders such as schizophrenia, depression, and bipolar disorder first appear. Additionally, the constant increase in life expectancy has led to a significant rise in the risk of several neurodegenerative disorders such as Parkinson’s disease (PD) and Alzheimer’s disease (AD). A primary research goal of neuroscience is to decipher the molecular mechanisms that play direct roles in the pathophysiology of brain disorders, including those of the young and old alike. Research into these mechanisms will have the most significant impact on brain diseases and mental health. The focal adhesion kinase (FAK) and its homologous FAK-related proline-rich tyrosine kinase 2 (Pyk2) define a distinct family of non-receptor tyrosine kinases that are predominantly expressed in the developing as well as in the adult brain. Despite their high similarity, they are believed to fulfill distinct roles within the brain, which are partially determined by their different expression patterns, localization, and interacting proteins. Here, we provide a comprehensive and up-to-date overview of all known neuronal interactors and signaling pathways in which Pyk2 and FAK are involved. Using bioinformatics analysis and statistical tools, we validate, for the first time, the long-term hypothesis by which FAK is involved in axonal guidance and neurodevelopmental signaling, while Pyk2 has a more prominent role in functions of the adult brain, such as memory and learning. We also characterize two new and previously unidentified roles of Pyk2 in neuropathic pain signaling and neuroinflammation. Correlation of the most significant pathways for each kinase with human brain disorders revealed the involvement of Pyk2 in neurodegenerative diseases such as PD, AD, Huntington’s disease (HD), and schizophrenia, while FAK was found to be mostly related to neurodevelopmental disorders in which axonal guidance plays a major role, and to a lesser extent to amyotrophic lateral sclerosis (ALS), schizophrenia, mood disorders, and AD. The involvement of FAK in these non-developmental pathways may suggest its possible role in compensating for Pyk2 in specific processes and/or brain disorders. Understanding the molecular mechanisms underlying regulation of FAK family proteins in brain and behavior may lead to novel therapeutic approaches for preventing or treating the underlying causes of neurodevelopmental abnormalities, psychiatric disorders, and neurodegenera
{"title":"FAK family kinases in brain health and disease","authors":"Kolluru D. Srikanth, T. Meirson, D. S. Sams, H. Gil-Henn","doi":"10.31083/J.JMCM.2018.03.007","DOIUrl":"https://doi.org/10.31083/J.JMCM.2018.03.007","url":null,"abstract":"Brain disorders are now identified as one of the largest and costliest health risks throughout human life. While most brain disorders are not life threatening per se, their chronic and incurable nature renders the overall burden from these disorders much greater than would be suggested by mortality figures alone. Several neurodevelopmental conditions, including autism and dyslexia, are being diagnosed at increasing rates throughout the last few decades. Adolescence is now well recognized as a vulnerable brain developmental phase, in which mental disorders such as schizophrenia, depression, and bipolar disorder first appear. Additionally, the constant increase in life expectancy has led to a significant rise in the risk of several neurodegenerative disorders such as Parkinson’s disease (PD) and Alzheimer’s disease (AD). A primary research goal of neuroscience is to decipher the molecular mechanisms that play direct roles in the pathophysiology of brain disorders, including those of the young and old alike. Research into these mechanisms will have the most significant impact on brain diseases and mental health. The focal adhesion kinase (FAK) and its homologous FAK-related proline-rich tyrosine kinase 2 (Pyk2) define a distinct family of non-receptor tyrosine kinases that are predominantly expressed in the developing as well as in the adult brain. Despite their high similarity, they are believed to fulfill distinct roles within the brain, which are partially determined by their different expression patterns, localization, and interacting proteins. Here, we provide a comprehensive and up-to-date overview of all known neuronal interactors and signaling pathways in which Pyk2 and FAK are involved. Using bioinformatics analysis and statistical tools, we validate, for the first time, the long-term hypothesis by which FAK is involved in axonal guidance and neurodevelopmental signaling, while Pyk2 has a more prominent role in functions of the adult brain, such as memory and learning. We also characterize two new and previously unidentified roles of Pyk2 in neuropathic pain signaling and neuroinflammation. Correlation of the most significant pathways for each kinase with human brain disorders revealed the involvement of Pyk2 in neurodegenerative diseases such as PD, AD, Huntington’s disease (HD), and schizophrenia, while FAK was found to be mostly related to neurodevelopmental disorders in which axonal guidance plays a major role, and to a lesser extent to amyotrophic lateral sclerosis (ALS), schizophrenia, mood disorders, and AD. The involvement of FAK in these non-developmental pathways may suggest its possible role in compensating for Pyk2 in specific processes and/or brain disorders. Understanding the molecular mechanisms underlying regulation of FAK family proteins in brain and behavior may lead to novel therapeutic approaches for preventing or treating the underlying causes of neurodevelopmental abnormalities, psychiatric disorders, and neurodegenera","PeriodicalId":92248,"journal":{"name":"Journal of molecular medicine and clinical applications","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2018-09-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"84934948","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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