Publications by authors named "Guiting Lin"

156 Publications

Mineralized Peyronie's plaque has a phenotypic resemblance to bone.

Acta Biomater 2021 Nov 21. Epub 2021 Nov 21.

Division of Biomaterials and Bioengineering, Department of Preventative and Restorative Dental Sciences, School of Dentistry, University of California San Francisco, California, United States of America; Department of Urology, School of Medicine, University of California, San Francisco, California, United States of America. Electronic address:

Mineralized Peyronie's plaque (MPP) impairs penile function. The association, colocalization, and dynamic interplay between organic and inorganic constituents can provide insights into biomineralization of Peyronie's plaque. Human MPPs (n = 11) were surgically excised, and the organic and inorganic constituents were spatially mapped using multiple high-resolution imaging techniques. Multiscale image analyses resulted in spatial colocalization of elements within a highly porous material with heterogenous composition, lamellae, and osteocytic lacuna-like features with a morphological resemblance to bone. The lower (520 ±179 mg/cc) and higher (1024 ± 155 mg/cc) mineral density regions were associated with higher (11%) and lower (7%) porosities in MPP. Energy dispersive X-ray and micro-X-ray fluorescent spectroscopic maps in the higher mineral density regions of MPP revealed higher counts of calcium (Ca) and phosphorus (P), and a Ca/P ratio of 1.48 ± 0.06 similar to bone. More importantly, higher counts of zinc (Zn) were localized at the interface between softer (more organic to inorganic ratio) and harder (less organic to inorganic ratio) tissue regions of MPP and adjacent softer matrix, indicating the involvement of Zn-related proteins and/or pathways in the formation of MPP. In particular, dentin matrix protein-1 (DMP-1) was colocalized in a matrix rich in proteoglycans and collagen that contained osteocytic lacuna-like features. This combined materials science and biochemical with correlative microspectroscopic approach provided insights into the plausible cellular and biochemical pathways that incite mineralization of an existing fibrous Peyronie's plaque. STATEMENT OF SIGNIFICANCE: Aberrant human penile mineralization is known as mineralized Peyronie's plaque (MPP) and often results in a loss of form and function. This study focuses on investigating the spatial association of matrix proteins and elemental composition of MPP by colocalizing calcium, phosphorus, and trace metal zinc with dentin matrix protein 1 (DMP-1), acidic proteoglycans, and fibrillar collagen along with the cellular components using high resolution correlative microspectroscopic techniques. Spatial maps provided insights into cellular and biochemical pathways that incite mineralization of fibrous Peyronie's plaque in humans.
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http://dx.doi.org/10.1016/j.actbio.2021.11.025DOI Listing
November 2021

Microenergy acoustic pulses promotes muscle regeneration through in situ activation of muscle stem cells.

J Orthop Res 2021 Oct 17. Epub 2021 Oct 17.

Department of Orthopaedic Surgery, San Francisco Veterans Affair Health Care System, San Francisco, California, USA.

Microenergy acoustic pulses (MAP) is a modified low-intensity extracorporeal shock wave therapy that currently used for treating musculoskeletal disorders. However, its function on muscle regeneration after ischemia-reperfusion injury (IRI) remains unknown. This study aimed to explore the effect of MAP on muscle injury after IRI and its underlying mechanisms. Ten-week-old C57BL/6J mice underwent unilateral hindlimb IRI followed with or without MAP treatment. Wet weight of tibialis anterior muscles at both injury and contralateral sides were measured followed with histology analysis at 3 weeks after IRI. In in vitro study, the myoblasts, endothelial cells and fibro-adipogenic progenitors (FAP) were treated with MAP. Cell proliferation and differentiation were assessed, and related gene expressions were measured by real-time PCR. Our results showed that MAP significantly increased the muscle weight and centrally nucleated regenerating muscle fiber size along with a trend in activating satellite cells. In vitro data indicated that MAP promoted myoblast proliferation and differentiation and endothelial cells migration. MAP also induced FAP brown/beige adipogenesis, a promyogenic phenotype of FAPs. Our findings demonstrate the beneficial function of MAP in promoting muscle regeneration after IR injury by inducing muscle stem cells proliferation and differentiation.
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http://dx.doi.org/10.1002/jor.25184DOI Listing
October 2021

Corrigendum to "Physicochemical and biochemical spatiotemporal maps of a mouse penis". [J. Biomech. 101 (2020) 109637].

J Biomech 2021 Aug 25;125:110563. Epub 2021 Jun 25.

Division of Biomaterials and Bioengineering, Department of Preventive and Restorative Dental Sciences, School of Dentistry, University of California San Francisco, San Francisco, CA, United States; Department of Urology, School of Medicine, University of California San Francisco, San Francisco, CA, United States. Electronic address:

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http://dx.doi.org/10.1016/j.jbiomech.2021.110563DOI Listing
August 2021

Low-intensity pulsed ultrasound stimulates proliferation of stem/progenitor cells: what we need to know to translate basic science research into clinical applications.

Asian J Androl 2021 Nov-Dec;23(6):602-610

Knuppe Molecular Urology Laboratory, Department of Urology, School of Medicine, University of California, San Francisco, CA 94143, USA.

Low-intensity pulsed ultrasound (LIPUS) is a promising therapy that has been increasingly explored in basic research and clinical applications. LIPUS is an appealing therapeutic option as it is a noninvasive treatment that has many advantages, including no risk of infection or tissue damage and no known adverse reactions. LIPUS has been shown to have many benefits including promotion of tissue healing, angiogenesis, and tissue regeneration; inhibition of inflammation and pain relief; and stimulation of cell proliferation and differentiation. The biophysical mechanisms of LIPUS remain unclear and the studies are ongoing. In recent years, more and more research has focused on the relationship between LIPUS and stem/progenitor cells. A comprehensive search of the PubMed and Embase databases to July 2020 was performed. LIPUS has many effects on stem cells. Studies show that LIPUS can stimulate stem cells in vitro; promote stem cell proliferation, differentiation, and migration; maintain stem cell activity; alleviate the problems of insufficient seed cell source, differentiation, and maturation; and circumvent the low efficiency of stem cell transplantation. The mechanisms involved in the effects of LIPUS are not fully understood, but the effects demonstrated in studies thus far have been favorable. Much additional research is needed before LIPUS can progress from basic science research to large-scale clinical dissemination and application.
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http://dx.doi.org/10.4103/aja.aja_25_21DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8577250PMC
April 2021

Regenerating Urethral Striated Muscle by CRISPRi/dCas9-KRAB-Mediated Myostatin Silencing for Obesity-Associated Stress Urinary Incontinence.

CRISPR J 2020 12;3(6):562-572

Knuppe Molecular Urology Laboratory, Department of Urology, School of Medicine, University of California, San Francisco, California, USA; Department of Chemical and Systems Biology, ChEM-H, Stanford University, Stanford, California, USA.

Overweight females are prone to obesity-associated stress urinary incontinence (OA-SUI), and there are no definitive medical therapies for this common urologic condition. This study was designed to test the hypothesis that regenerative therapy to restore urethral striated muscle (stM) and pelvic floor muscles might represent a valuable therapeutic approach. For the experiment, single-guide RNAs targeting myostatin () were used for CRISPRi/dCas9-Kruppel associated box (KRAB)-mediated gene silencing. For the experiment, a total of 14 female lean ZUC-Lepr 186 and 14 fatty ZUC-Lepr 185 rats were used as control and CRISPRi-MSTN treated groups, respectively. The results indicated that lentivirus-mediated expression of MSTN CRISPRi/dCas9-KRAB caused sustained downregulation of MSTN in rat L6 myoblast cells and significantly enhanced myogenesis . , the urethral sphincter injection of lentiviral-MSTN sgRNA and lentiviral-dCas9-KRAB significantly increased the leak point pressure, the thickness of the stM layer, the ratio of stM to smooth muscle, and the number of neuromuscular junctions. Downregulation of with CRISPRi/dCas9-KRAB-mediated gene silencing significantly enhanced myogenesis and It also improved urethral continence in the OA-SUI rat model.
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http://dx.doi.org/10.1089/crispr.2020.0077DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7757699PMC
December 2020

Molecular mechanism of action of low-intensity extracorporeal shockwave therapy for regenerating penile and peripheral nerves.

Turk J Urol 2020 Oct 9. Epub 2020 Oct 9.

Knuppe Molecular Urology Laboratory, Department of Urology, School of Medicine, University of California, San Francisco, USA.

Sufficient functional repair of damaged peripheral nerves is a big clinical challenge in terms of long-lasting morbidity, disability, and economic costs. Nerve damage after radical prostatectomy is the most common cause of erectile dysfunction (ED). In recent years, low-intensity extracorporeal shockwave therapy (Li-ESWT) has been explored to improve the outcomes of peripheral nerve repair and regeneration. Research indicated that application of Li-ESWT after nerve surgery promoted nerve regeneration and improved the functional outcomes, underlined the mechanisms related to increase of neurotrophic factors, Schwann cells activation, and cellular signaling activation for cell activation and mitosis induced by Li-ESWT. We searched PubMed for articles related to research on these topics in both in vitro and in vivo animal models and found numerous studies suggesting that the application Li-ESWT could be a novel treatment for ED induced by nerve injury and other disease related to nerve injury.
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http://dx.doi.org/10.5152/tud.2020.20419DOI Listing
October 2020

Evaluation of the In Vitro Damage Caused by Lipid Factors on Stem Cells from a Female Rat Model of Type 2 Diabetes/Obesity and Stress Urinary Incontinence.

Int J Mol Sci 2020 Jul 17;21(14). Epub 2020 Jul 17.

Division of Urology, Department of Surgery, Harbor-UCLA Medical Center and The Lundquist Institute at Harbor-UCLA Medical Center, Torrance, CA 90502, USA.

Human stem cell therapy for type 2 diabetes/obesity (T2D/O) complications is performedwith stem cell autografts, exposed to the noxious T2D/O milieu, often with suboptimal results.We showed in the Obese Zucker (OZ) rat model of T2D/O that when their muscle-derived stemcells (MDSC) were from long-term T2D/O male rats, their repair ecacy for erectile dysfunctionwas impaired and were imprinted with abnormal gene- and miR-global transcriptional signatures(GTS). The damage was reproduced in vitro by short-term exposure of normal MDSC to dyslipidemicserum, causing altered miR-GTS, fat infiltration, apoptosis, impaired scratch healing, and myostatinoverexpression. Similar in vitro alterations occurred with their normal counterparts (ZF4-SC) fromthe T2D/O rat model for female stress urinary incontinence, and with ZL4-SC from non-T2D/O leanfemale rats. In the current work we studied the in vitro eects of cholesterol and Na palmitate aslipid factors on ZF4-SC and ZL4-SC. A damage partially resembling the one caused by the femaledyslipidemic serum was found, but diering between both lipid factors, so that each one appears tocontribute specifically to the stem cell damaging eects of dyslipidemic serum in vitro and T2D/Oin vivo, irrespective of gender. These results also confirm the miR-GTS biomarker value forMDSC damage.
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http://dx.doi.org/10.3390/ijms21145045DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7404394PMC
July 2020

Probucol enhances the therapeutic efficiency of mesenchymal stem cells in the treatment of erectile dysfunction in diabetic rats by prolonging their survival time via Nrf2 pathway.

Stem Cell Res Ther 2020 07 21;11(1):302. Epub 2020 Jul 21.

Department of Urology, Shandong Provincial Hospital, Cheeloo College of Medicine, Shandong University, Jingwuweiqi Road 324#, Jinan, 250021, Shandong, People's Republic of China.

Background: Intracavernous injection of mesenchymal stem cells (MSCs) is a promising method for diabetic mellitus-induced erectile dysfunction (DMED), but short survival time of MSCs in cavernous is a fatal defect for therapy. This study investigated therapeutic efficiency and potential mechanism of probucol combined with MSCs.

Methods: In vivo study, a total of forty-eight 10-week-old male Sprague-Dawley (SD) rats were used. Twelve rats received intraperitoneal injection of PBS as the sham group; the rest received intraperitoneal injection of 60 mg/kg streptozotocin to establish DM models. DM rats were randomly divided into three groups: received intracavernosal (IC) injection of either PBS (DM group), MSCs (M group), or administrated probucol after intracavernosal injection of MSCs (P + M group). Erectile function was assessed by electrical stimulation of the cavernous nerves with real-time intracavernous pressure measurement. After euthanasia, penile tissue was investigated for histologic examination and Western blotting. In in vitro experiment, HO was used to create oxidative stress environment to detect changes in cell viability. CCK8 was used to measure cell viability of MSCs treated with or without probucol. Intracellular ROS changes were detected by flow cytometry. Autophagy and apoptosis were detected by Western blotting and confocal microscopy.

Results: Recovery of erectile function was observed in the P + M group. The combination therapy decreased fibrosis and increased endothelial function compared with MSC therapy alone. Western blotting results confirmed the increased expression of Nrf2 and HO-1 in cavernous body. HO induced high oxidative stress and reduced cell viability in vitro, which was gradually reversed with increased concentration of probucol. HO reduced Nrf2 expression, which was reversed by probucol's intervention. Furthermore, the expression of Bax, Caspase3, and Cleaved-Caspase3 decreased, and the expression of Bcl-2 increased in a dose-dependent manner because of probucol's intervention. In addition, Beclin1 and LC3II both increased in a dose-dependent manner. Meanwhile, the expression of P62 decreased. In the study of autophagy flux, we found probucol did not block it.

Conclusion: Probucol enhanced therapeutic efficiency of MSCs in DMED by prolonging their survival time, which mediated through improving the transplanted microenvironment of MSCs, increasing self-antioxidant ability of MSCs, strengthening protective autophagy, and inhibiting apoptosis of MSCs via Nrf2 pathway. Schematic model showing combined probucol and MSCs to improve DMED. Probucol increases self-antioxidant ability of MSCs, strengthening protective autophagy and inhibiting apoptosis via Nrf2/HO-1 and Nrf2/autophagy pathways.
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http://dx.doi.org/10.1186/s13287-020-01788-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7374958PMC
July 2020

Exosome Released From Schwann Cells May Be Involved in Microenergy Acoustic Pulse-Associated Cavernous Nerve Regeneration.

J Sex Med 2020 09 12;17(9):1618-1628. Epub 2020 Jul 12.

Knuppe Molecular Urology Laboratory, Department of Urology, School of Medicine, University of California, San Francisco, CA, USA. Electronic address:

Background: Neurogenic erectile dysfunction (ED) is often refractory to treatment because of insufficient functional nerve recovery after injury or insult. Noninvasive mechano-biological intervention, such as microenergy acoustic pulse (MAP), low-intensity pulsed ultrasound, and low-intensity extracorporeal shockwave treatment, is an optimal approach to stimulate nerve regeneration.

Aim: To establish a new model in vitro to simulate nerve injury in neurogenic ED and to explore the mechanisms of MAP in vitro.

Methods: Sprague-Dawley rats were used to isolate Schwann cells (SCs), major pelvic ganglion (MPG), and cavernous nerve with MPG (CN/MPG). SCs were then treated with MAP (0.033 mJ/mm, 1 Hz, 100 pulses), and SC exosomes were isolated. The MPG and CN/MPG were treated with MAP (0.033 mJ/mm, 1 Hz) at different dosages (25, 50, 100, 200, or 300 pulses) or exosomes derived from MAP-treated SCs in vitro.

Outcomes: Neurite growth from the MPG fragments and CN was photographed and measured. Expression of neurotropic factors (brain-derived neurotrophic factor, nerve growth factor, and neurotrophin-3) was checked.

Results: Neurite outgrowth from MPG and CN/MPG was enhanced by MAP in a dosage response manner, peaking at 100 pulses. MAP promoted SC proliferation, neurotropic factor (brain-derived neurotrophic factor, nerve growth factor, and neurotrophin-3) expression, and exosome secretion. SC-derived exosomes significantly enhanced neurite outgrowth from MPG in vitro.

Clinical Implications: MAP may have utility in the treatment of neurogenic ED by SC-derived exosomes.

Strength & Limitations: We confirmed that MAP enhances penile nerve regeneration through exsomes. Limitations of this study include that our study did not explore the exact mechanisms of how MAP increases SC exosome secretion nor whether MAP modulates the content of exosomes.

Conclusion: This study revealed that neurite outgrowth from MPG was enhanced by MAP and by SC-derived exosomes which were isolated after MAP treatment. Our findings indicate that one mechanism by which MAP induces nerve regeneration is by stimulation of SCs to secrete exosomes. Peng D, Reed-Maldonado AB, Zhou F, et al. Exosome Released From Schwann Cells May Be Involved in Microenergy Acoustic Pulse-Associated Cavernous Nerve Regeneration. J Sex Med 2020;17:1618-1628.
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http://dx.doi.org/10.1016/j.jsxm.2020.05.018DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7483773PMC
September 2020

Administration of secretome from human placental stem cell-conditioned media improves recovery of erectile function in the pelvic neurovascular injury model.

J Tissue Eng Regen Med 2020 10 31;14(10):1394-1402. Epub 2020 Jul 31.

Wake Forest Institute for Regenerative Medicine, Winston-Salem, NC, USA.

Human placental stem cells (PSCs) enhance histological and functional recovery in a rodent erectile dysfunction (ED) model. We tested the hypothesis that bioactive factors secreted by PSC (i.e., the secretome) mediate functional recovery and that acellular-conditioned media (CM) from PSC culture (PSC-CM) could be used independently to facilitate functional and histological recovery. To identify factors relative to efficacy of PSC, a comparison of CM from PSC and three additional human stem cell populations was performed. CM from human PSC, amniotic fluid stem cells (AFSCs), adipose-derived stem cells (ADSC), and human umbilical vein endothelial cells (HUVECs) was assayed using a semi-quantitative human cytokine antibody array. Male rats, after surgically created ED by neurovascular injury, were randomly divided into four groups: vehicle control (phosphate-buffered saline [PBS]), PSC, PSC-CM, and serum-free media control (SFM) as control. Functional data on intracorporal and mean arterial pressure were obtained, and histological architecture was examined 6 weeks after single injection. PSCs were found to secrete at least 27 cytokines and growth factors at a significantly higher level than the other three cell types. Either single injection of PSC-CM or PSC significantly improved erectile functional recovery and histological architecture compared with SFM or PBS. Injection of the secretome isolated from human PSC improves erectile functional recovery and histological structure in a rat model of neurovascular injury-induced ED. Further characterization of the unique protein expression within the PSC-CM may help to identify the potential for a novel injectable cell-free therapeutic for applicable patients.
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http://dx.doi.org/10.1002/term.3105DOI Listing
October 2020

Estimates of over-time trends in incidence and mortality of prostate cancer from 1990 to 2030.

Transl Androl Urol 2020 Apr;9(2):196-209

School of Public Health, Tianjin Medical University, Tianjin 300070, China.

Background: This research aims to identify the current and future trends in the incidence and death rate of prostate cancer and to provide the necessary data support for making relevant health decisions.

Methods: This study used the collected data and methodologies to describe the incidence and mortality trends of prostate cancer from 1990 to 2016. Based on the data, this paper projected the future trends in prostate cancer incidence and death rate.

Results: In 2016, prostate cancer cases [1,435,742; 95% uncertainty interval (UI), 1,293,395-1,618,655] were nearly 2.5-fold the number in 1990 (579,457; 95% UI, 521,564-616,107). Deaths increased by 2.0-fold from 191,687 (95% UI, 168,885-209,254) in 1990 to 380,916 (95% UI, 320,808-412,868) in 2016. The global age-standardized incidence rate (ASIR) increased from 17.75 (95% UI, 18.91-15.95) in 1990 to 22.12 (95% UI, 19.92-24.91) in 2016, changing 24.62%. The global change of age-standardized death rate (ASDR) has declined slightly, but in some regions it shows a trend of growth. By sociodemographic index (SDI) sub-types, prostate cancer will frequently occur in high SDI countries from 1990 to 2030. Simultaneously, the highest mortality will present in low SDI countries.

Conclusions: Through projecting and analyzing incidence and mortality rate of prostate cancer, from 1990 to 2030, by different ages, regions and SDI sub-types, this result may reveal the relationship between prostate cancer and financial development. At the same time, the result also showed a sufficiently heavy burden of prostate cancer, but the burden varies greatly in each region. The burden is a challenge and will require attention for all levels of society. The current study is beneficial to formulate more specific and efficient policies.
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http://dx.doi.org/10.21037/tau.2020.02.21DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7214983PMC
April 2020

Estimates of over-time trends in incidence and mortality of testicular cancer from 1990 to 2030.

Transl Androl Urol 2020 Apr;9(2):182-195

School of Public Health, Tianjin Medical University, Tianjin 300070, China.

Background: This study aims to explore and project the temporal trends in incidence and mortality of testicular cancer. Moreover, it can provide theoretical guidance for the rational allocation of health resources.

Methods: This study analyzed existing data on testicular cancer morbidity and mortality from 1990 to 2016 and predicted time-varying trends of age-standardized incidence rate (ASIR) and age-standardized death rate (ASDR) from 2017 to 2030 in different ages, regions and sociodemographic index (SDI) quintile sub-groups.

Result: Globally, numbers of testicular cancer cases in 2016 [66,833; 95% uncertainty interval (UI), 64,487-69,736] are 1.8 times larger than in 1990 (37,231; 95% UI, 36,116-38,515). The testicular cancer-related death cases increased slightly from 8,394 (95% UI, 7,980-8,904) in 1990 to 8,651 (95% UI, 8,292-9,027) in 2016. In aspect of ASIR, the data showed an up-trend from 0.74 (95% UI, 0.72-0.77) in 1990 to 0.88 (95% UI, 0.85-0.92) in 2016. The ASDR of testicular cancer declined from 0.18 (95% UI, 0.17-0.19) in 1990 to 0.12 (95% UI, 0.11-0.12) in 2016. From 2017 to 2030, predictions of trends in testicular cancer indicate that the ASIRs of most SDI countries are rising, but the ASDRs trends in testicular cancer will decrease.

Conclusions: By analyzing the available and reliable data in different ages, regions and SDI, this study shows a significant upward trend in incidence and a slow upward trend in mortality of testicular cancer from 1990 to 2016, and simultaneously, predicts the increase of ASIR and the downward trend of ASDR in 2017-2030.
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http://dx.doi.org/10.21037/tau.2020.02.22DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7215014PMC
April 2020

Temporal trends of kidney cancer incidence and mortality from 1990 to 2016 and projections to 2030.

Transl Androl Urol 2020 Apr;9(2):166-181

School of Public Health, Tianjin Medical University, Tianjin 300070, China.

Background: This study aims to present the trends of incidence and mortality of kidney cancer from 1990 to 2016 by age, gender, geographical region, regional, and sociodemographic index (SDI), and then forecast the future trends to 2030.

Methods: Data of this study were gathered from the Global Burden of Disease Study (GBD), including 195 countries and territories, accounting for 21 regions. Over-time trends from 1990 to 2016 were analyzed by gender, geographical region, age range and SDI. Based on the big data, we forecasted the future trends to 2030 by ARIMA model. All the data were analyzed by R software (x64 version 3.5.1), SAS (version 9.3) and SPSS (version 22.0).

Results: Globally, in 2016, there were 342,100 [95% uncertainty interval (UI), 330,759-349,934] incident cases of kidney cancer and the number of deaths were 131,800 (127,335-136,185). The age-standardized incidence rate (ASIR) and death rate (ASDR) were 4.97 (4.81-5.09) per 100,000 and 2.00 (1.93-2.06) per 100,000, respectively. Globally, the estimated risk of kidney cancer for male within the age of 30 and 70 is around 0.79% compared to 0.41% for female. In other words, the probability of developing kidney cancer was generally higher in male than in female. By 2030, incidence of kidney cancer in both sexes are projected to increase substantially in high SDI, followed by middle SDI, low-middle SDI, and low SDI countries. High SDI and low SDI countries will also have increased mortality rates of kidney cancers. Globally, the trends in deaths due to kidney cancer will remain stable.

Conclusions: The incidence and death rate of kidney cancer are highly variable among SDI countries and regions but have increased uniformly from 1990 to 2016. By 2030, the future incidence of kidney cancer will grow continuously especially in high SDI countries, middle SDI, low-middle SDI, and low SDI countries.
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http://dx.doi.org/10.21037/tau.2020.02.23DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7215038PMC
April 2020

Temporal trends of bladder cancer incidence and mortality from 1990 to 2016 and projections to 2030.

Transl Androl Urol 2020 Apr;9(2):153-165

School of Public Health, Tianjin Medical University, Tianjin 300070, China.

Background: Bladder cancer is a leading cause of cancer-related deaths all over the world. Epidemiological studies of bladder cancer are therefore crucial for policy making. This study was carried out to describe the characteristics of changes in the incidence and mortality of bladder cancer from 1990 to 2016 by age group, gender, geographical region, and sociodemographic index (SDI) and to simultaneously project future trends up to 2030.

Methods: Incidence and mortality trends in bladder cancer from 1990 to 2016 were described based on data and methodologies from the Global Burden of Disease (GBD) Study. The data also allowed the future trends of bladder cancer incidence and mortality to be predicted by ARIMA model. Trends were analyzed by age group, gender, and SDI. Projections to 2030 were sub-analyzed by SDI countries. R software (x64 version 3.5.1), SAS (version 9.3), and SPSS (version 22.0) were used throughout the process.

Results: Globally, in 2016, there were 437,442 [95% uncertainty interval (UI), 426,709-447,912] new bladder cancer cases and 186,199 (95% UI, 180,453-191,686) bladder cancer-associated deaths. Between 1990 and 2016, changes in the age-standardized incidence rate (ASIR) of bladder cancer decreased by 5.91% from 7.11 (95% UI, 6.93-7.27) in 1990 to 6.69 (95% UI, 6.52-6.85) in 2016. The age-standardized death rate (ASDR) decreased from 3.58 (95% UI, 3.49-3.68) to 2.94 (95% UI, 2.85-3.03) over the same period of time. In future, the greatest occurrence of bladder cancer will be in high SDI countries, followed by high-middle SDI countries. Moreover, bladder cancer incidence rates may increase substantially in middle SDI countries, while the incidence rates will remain relatively stable for men and women in other SDI countries. From 2017 to 2030, bladder cancer deaths will continue to increase in low SDI countries, while deaths in other SDI countries will continue to decrease.

Conclusions: There was a regional difference in the incidence and mortality trends of bladder cancer between 1990 and 2016. Overall, the situation is not optimistic. From 2017 to 2030, the incidence of bladder cancer will continue to rise, especially in high and high-middle SDI countries, where decision-makers should propose appropriate policies on the screening and prevention of bladder cancer.
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http://dx.doi.org/10.21037/tau.2020.02.24DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7215039PMC
April 2020

Delayed Treatment With Low-intensity Extracorporeal Shock Wave Therapy in an Irreversible Rat Model of Stress Urinary Incontinence.

Urology 2020 Jul 10;141:187.e1-187.e7. Epub 2020 Apr 10.

Department of Urology, Knuppe Molecular Urology Laboratory, School of Medicine, University of California, San Francisco, CA. Electronic address:

Objective: To determine the outcomes and mechanisms of delayed low-intensity extracorporeal shock wave therapy (Li-ESWT) in a rat model of irreversible stress urinary incontinence (SUI).

Materials And Methods: Twenty-four female Sprague-Dawley rats were randomly assigned into 3 groups: sham control, vaginal balloon dilation + β-aminopropionitrile (BAPN; SUI group), and vaginal balloon dilation + BAPN + treatment with Li-ESWT (SUI-Li-ESWT group). An irreversible SUI model was developed by inhibiting the urethral structural recovery with BAPN daily for 5 weeks. Thereafter, in the SUI-Li-ESWT group, Li-ESWT was administered twice per week for 2 weeks. After a 1-week washout, all 24 rats were evaluated with functional and histologic studies at 17 weeks of age. Endogenous progenitor cells were detected via the EdU-labeling method.

Results: Functional analysis with leak point pressure testing showed that the SUI-Li-ESWT group had significantly higher leak point pressures compared with untreated rats. Increased urethral and vaginal smooth and striated muscle content and increased thickness of the vaginal wall were noted in the SUI-Li-ESWT group. The SUI group had significantly decreased neuronal nitric oxide /tyrosine hydroxylase positive nerves ratio in the smooth muscle layers of the urethra, while the SUI-Li-ESWT group had neuronal nitric oxide/tyrosine hydroxylase+ nerves ratio similar to that of the control group. The continuality of urothelial cell lining was also improved in the SUI-Li-ESWT group. In addition, there were significantly increased EdU-positive cells in the SUI-Li-ESWT group.

Conclusion: Li-ESWT appears to increase smooth muscle content in the urethra and the vagina, increase the thickness of urethral wall, improve striated muscle content and neuromuscular junctions, restore the integrity of the urothelium, and increase the number of EdU-retaining progenitor cells in the urethral wall.
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http://dx.doi.org/10.1016/j.urology.2020.03.035DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7321915PMC
July 2020

Microenergy acoustic pulses induced myogenesis of urethral striated muscle stem/progenitor cells.

Transl Androl Urol 2019 Oct;8(5):489-500

Knuppe Molecular Urology Laboratory, Department of Urology, School of Medicine, University of California, San Francisco, CA, USA.

Background: Stress urinary incontinence (SUI) is a common disorder with high prevalence in women across their life span, but there are no non-surgical curative options for the condition. Stem cell-based therapy, especially endogenous stem cell therapy may be a potential treatment method for SUI. The aims of this study are to identify, isolate, and assay the function of urethral striated muscle derived stem/progenitor cells (uMDSCs) and to assess uMDSC response to microenergy acoustic pulses (MAP).

Methods: Urethral striated muscle was identified utilizing 3D imaging of solvent organs (3DISCO) and immunofluorescence (IF). uMDSCs were isolated and purified from Zucker Lean (ZL) (ZUC-LEAN) (ZUC-Leprfa 186) rats, with magnetic-activated cell sorting (MACS) and pre-plating methods. The stemness and differentiation potential of the uMDSCs were measured by cell proliferation, EdU, flow cytometry, IF, and Western blot.

Results: Comparison of the cell proliferation assays between MACS and pre-plating reveals the advantage of MACS over pre-plating. In addition, the study reveals that uMDSCs form myotubes when treated with MAP.

Conclusions: The uMDSCs within female rat urethral striated muscle could be a therapeutic target of MAP in managing SUI.
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http://dx.doi.org/10.21037/tau.2019.08.18DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6842786PMC
October 2019

Physicochemical and biochemical spatiotemporal maps of a mouse penis.

J Biomech 2020 03 16;101:109637. Epub 2020 Jan 16.

Division of Biomaterials and Bioengineering, Department of Preventive and Restorative Dental Sciences, School of Dentistry, University of California San Francisco, San Francisco, CA, United States; Department of Urology, School of Medicine, University of California San Francisco, San Francisco, CA, United States. Electronic address:

Spatiotemporal mechanobiology resulting in penile pathologies continues to be investigated using small scale animals models such as mice. However, species-dependent functional biomechanics of a mouse penis, is not known. In this study, spatial mapping of a mechanosensitive transcription factor, scleraxis (Scx), at ages 4, 5, 6 weeks, and 1 year were generated to identify mechanoactive regions within penile tissues. Reconstructed volumes of baculum collected using micro X-ray computed tomography illustrated significantly increased baculum length with decreased porosity, and increased mineral density (p < 0.05) with age. The bony-baculum was held centrally in the Scx positive corpus cavernosum glandis (CCG), indicating mechanoactivity within the struts in a 6 week old mouse. The struts also were stained positive for fibrillar proteins including collagen and elastin, and globular proteins including protein gene product 9.5, and α-smooth muscle actin. The corpus cavernosum penis (CCP) contained significantly (p < 0.05) more collagen than CCG within the same penis, and both regions contained blood vessels with equivalent innervation at any given age. Comparison of volumes of flaccid and erect penile forms revealed functional characteristics of the CCP. Results of this study provided insights into biomechanical function of the CCG; in that, it is a high-pressure chamber that stiffens the penis and is similar to the human corpus cavernosum.
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http://dx.doi.org/10.1016/j.jbiomech.2020.109637DOI Listing
March 2020

Dynamic Changes in Erectile Function and Histological Architecture After Intracorporal Injection of Human Placental Stem Cells in a Pelvic Neurovascular Injury Rat Model.

J Sex Med 2020 03 27;17(3):400-411. Epub 2020 Jan 27.

Wake Forest Institute for Regenerative Medicine, Wake Forest School of Medicine, Winston-Salem, NC, USA. Electronic address:

Introduction: The human placenta provides a bountiful and noncontroversial source of stem cells which have the potential for regeneration of injured tissue. These cells may restore erectile function after neurovascular tissue injury such as that seen in radical pelvic surgeries and pelvic trauma.

Aim: To determine the effect of human placenta-derived stem cells on erectile function recovery and histological changes at various time points in a cavernous nerve injury rat model and to study the fate of injected stem cells throughout the regenerative process.

Methods: Human placental stem cells (PSCs) were dual labeled with monomeric Katushka far red fluorescent protein (mKATE)-renLUC using a lentivirus vector. A pelvic neurovascular injury-induced erectile dysfunction model was established in male, athymic rats by crushing the cavernous nerves and ligating the internal pudendal neurovascular bundles, bilaterally. At the time of defect creation, nonlabeled PSCs were injected into the corpus cavernosum at a concentration of 2.5 × 10 cells/0.2 mL. The phosphate-buffered saline-treated group served as the negative control group, and age-matched rats (age-matched controls) were used as the control group. Erectile function, histomorphological analyses, and Western blot were assessed at 1, 6, and 12 weeks after model creation. The distribution of implanted, dual-labeled PSCs was monitored using an in vivo imaging system (IVIS). Implanted cells were further tracked by detection of mKATE fluorescence in histological sections.

Main Outcome Measure: The main outcome measure includes intracavernous pressure/mean arterial pressure ratio, neural, endothelial, smooth muscle cell regeneration, mKATE fluorescence, and IVIS imaging.

Results: The ratio of intracavernous pressure to mean arterial pressure significantly increased in PSC-injected rats compared with phosphate-buffered saline controls (P < 0.05) at the 6- and 12-week time points, reaching 72% and 68% of the age-matched control group, respectively. Immunofluorescence staining and Western blot analysis showed significant increases in markers of neurons (84.3%), endothelial cells (70.2%), and smooth muscle cells (70.3%) by 6 weeks in treatment groups compared with negative controls. These results were maintained through 12 weeks. IVIS analysis showed luminescence of implanted PSCs in the injected corpora immediately after injection and migration of cells to the sites of injury, including the incision site and periprostatic vasculature by day 1. mKATE fluorescence data revealed the presence of PSCs in the penile corpora and major pelvic ganglion at 1 and 3 days postoperatively. At 7 days, immunofluorescence of penile PSCs had disappeared and was diminished in the major pelvic ganglion.

Clinical Implications: Placenta-derived stem cells may represent a future "off-the-shelf" treatment to mitigate against development of erectile dysfunction after radical prostatectomy or other forms of pelvic injury.

Strength & Limitations: Single dose injection of PSCs after injury resulted in maximal functional recovery and tissue regeneration at 6 weeks, and the results were maintained through 12 weeks. Strategies to optimize adult stem cell therapy might achieve more effective outcomes for human clinical trials.

Conclusion: Human PSC therapy effectively restores the erectile tissue and function in this animal model. Thus, PSC therapy may provide an attractive modality to lessen the incidence of erectile dysfunction after pelvic neurovascular injury. Further improvement in tissue regeneration and functional recovery may be possible using multiple injections or systemic introduction of stem cells. Gu X, Thakker PU, Matz EL, et al. Dynamic Changes in Erectile Function and Histological Architecture After Intracorporal Injection of Human Placental Stem Cells in a Pelvic Neurovascular Injury Rat Model. J Sex Med 2020;17:400-411.
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http://dx.doi.org/10.1016/j.jsxm.2019.12.002DOI Listing
March 2020

Development of Male External Urethral Sphincter and Tissue-Resident Stem/Progenitor Cells in Rats.

Stem Cells Dev 2020 02 6;29(3):133-143. Epub 2020 Jan 6.

Knuppe Molecular Urology Laboratory, Department of Urology, School of Medicine, University of California, San Francisco, California.

Stress urinary incontinence (SUI) after prostate surgery is primarily caused by urethral sphincter damage. There are few effective therapeutic approaches for male SUI due to both insufficient study of the structure of the external urethral sphincter (EUS) and incomplete understanding of the resident EUS stem/progenitor cells. The goals of this study were to localize and to determine the distribution of tissue-resident stem/progenitor cells in the male EUS throughout EUS development and to understand the anatomic temporal patterns of the EUS. Newborn Sprague Dawley rats were intraperitoneally injected with the thymidine analogue, 5-ethynyl-2-deoxyuridine (EdU), and the EUS was harvested at five time points (1, 2, 3, 4, and 8 weeks postinjection). The tissue was then processed for EdU staining and immunofluorescence staining for stem cell markers Ki67 and proliferating cell nuclear antigen. We counted the EdU+ label-retaining cells (LRCs) at each time point and colocalized with each stem cell marker, also we isolated and cultured the cells in vitro. The results revealed that the number of EdU+ LRCs in each EUS cross-section decreased over time and that the LRCs were located immediately under the basal membrane of laminin, densely adherent to the muscle fibers. In addition, the thickness of the striated muscle layer developed much faster than the smooth muscle layer during EUS development. By 4 weeks, the structure of the EUS layers was well differentiated. The EUS resident stem/progenitor cells were isolated with MACS MicroBeads system, and myogenesis was confirmed. In this study, we defined both the time-course development of the EUS and the distribution of resident stem/progenitor cells. This information is crucial for forthcoming studies regarding male micturition and for development of novel therapeutic approaches for postoperative male SUI.
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http://dx.doi.org/10.1089/scd.2019.0241DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6987740PMC
February 2020

Smooth Muscle Differentiation of Penile Stem/Progenitor Cells Induced by Microenergy Acoustic Pulses In Vitro.

J Sex Med 2019 12 1;16(12):1874-1884. Epub 2019 Oct 1.

Knuppe Molecular Urology Laboratory, Department of Urology, School of Medicine, University of California, San Francisco, CA, USA. Electronic address:

Introduction: Modulating tissue-resident stem and progenitor cells with a non-invasive, mechanobiological intervention is an optimal approach for tissue regeneration. Stem cell antigen-1 (Sca-1) has been identified as a stem cell marker within many organs but never within the penis.

Aim: To localize and isolate penile stem/progenitor cells (PSPCs) and to evaluate cellular differentiation after exposure to induction medium and microenergy acoustic pulse (MAP) therapy.

Methods: Six male Sprague-Dawley rats were used to isolate PSPCs. Isolation was followed by stem cell characterization and differentiation assays. The PSPCs were then treated with MAP (0.033 mJ/mm, 1 Hz) at various dosages (25, 50, 100, and 200 pulses) and for different durations (1, 2, 4, 6, or 8 hours) in vitro.

Main Outcome Measure: The PSPCs (Sca-1-positive cells) were isolated using the magnetic-activated cell sorting system. PSPC cellular differentiation was assessed after induction with induction medium and with MAP in vitro. Wnt/β-catenin signaling was also assayed.

Results: The PSPCs were successfully localized within the penile subtunic and perisinusoidal spaces, and they were successfully isolated using magnetic-activated cell sorting. The stemness of the cells was confirmed by stem cell marker characterization and by multiple differentiation into smooth muscle cells, endothelial cells, adipocytes, and neurons. MAP-induced PSPCs differentiated into smooth muscle cells by activating the Wnt/β-catenin signaling pathway in a time- and dosage-dependent manner.

Clinical Implications: By modulating resident PSPCs, MAP may have utility in the treatment of erectile dysfunction (ED).

Strengths & Limitations: This study provides solid evidence in support of microenergy therapies, including both MAP and low-intensity extracorporeal shock wave therapy, for the treatment of ED. Additional studies are needed and should include additional stem cells markers. Furthermore, studies exploring the underling mechanisms for PSPC activation and differentiation are required.

Conclusion: PSPCs were successfully identified, localized, and isolated. Additionally, MAP provoked PSPCs to differentiate into smooth muscle cells via the Wnt/β-catenin signaling pathway. As such, MAP provides a novel method for activating endogenous tissue-resident stem/progenitor cells and might facilitate stem cell regenerative therapy targeting ED. Peng D, Yuan H, Liu T, et al. Smooth Muscle Differentiation of Penile Stem/Progenitor Cells Induced by Microenergy Acoustic Pulses In Vitro. J Sex Med 2019; 16:1874-1884.
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http://dx.doi.org/10.1016/j.jsxm.2019.08.020DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6885549PMC
December 2019

Efficacy and safety of novel low-intensity pulsed ultrasound (LIPUS) in treating mild to moderate erectile dysfunction: a multicenter, randomized, double-blind, sham-controlled clinical study.

Transl Androl Urol 2019 Aug;8(4):307-319

Andrology Center, Peking University First Hospital, Beijing 100034, China.

Background: In our previous study, a novel low-intensity pulsed ultrasound (LIPUS) therapeutic device has been shown to improve erectile function non-invasively in a diabetic-induced erectile dysfunction (ED) animal model.

Methods: In order to investigate the efficacy and safety of LIPUS in the clinical treatment of patients with ED, a multicenter, randomized, double-blind, sham-treated, controlled clinical study was conducted at five medical centers, and 120 patients with mild to moderate ED were enrolled in the study. Patients were randomized into a sham-treated control group (40 patients) or a LIPUS-treated group (80 patients). LIPUS or sham treatment was applied to both sides of the penis shaft and crus for 5 min in each area, twice a week for four weeks. Assessment of efficacy and safety were evaluated using IIEF-5, Sexual Encounter Profile (SEP)-questionnaires 2/3, Global Assessment Question (GAQ), Erectile Hardness Score (EHS), Erection Quality Scale (EQS) score, and pain assessment [Visual Analogue Scale/Score (VAS)].

Results: Ten patients in LIPUS treatment group and 6 patients in sham treatment control group were excluded and the dropout rate is 13.33%. Response to treatment was identified as IIEF-5 score increased more than 2/3/4 points of post-treatment (12W) compared to pre-treatment (0W). The response rate in treatment group was 54/80 (67.50%), which was significantly higher than control group 8/40 (20.00%) at 12 weeks (FAS analysis). The percentage of patients with positive answers to SEP-3 (successful vaginal intercourse) were 58.97%, 64.1%, and 73.08% 4, 8, and 12 weeks after treatment which were significantly higher than 28.95%, 31.58%, and 28.95% respectively in control group (FAS, P<0.05). The positive responsive rates for GAQ in treatment group were about 2 to 3 times of that in control group (P<0.05). No treatment-related adverse events (AEs) were found, including local petechia or ecchymosis and hematuria.

Conclusions: Current study indicates that LIPUS can safely and effectively treat patients with mild to moderate ED without significant AEs, which is related to the mechanical force of LIPUS and can restore the pathological changes of the corpus cavernosum. LIPUS is a promising alternative treatment for ED treatment in the near future, while further research is remanded.
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http://dx.doi.org/10.21037/tau.2019.07.03DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6732092PMC
August 2019

The effects of microenergy acoustic pulses on an animal model of obesity-associated stress urinary incontinence. Part 1: Functional and histologic studies.

Neurourol Urodyn 2019 11 4;38(8):2130-2139. Epub 2019 Sep 4.

Knuppe Molecular Urology Laboratory, Department of Urology, School of Medicine, University of California, San Francisco, California.

Aim: Obesity is a strong independent risk factor for urinary incontinence. Effective therapeutic approaches for obesity-associated stress urinary incontinence (OA-SUI) are lacking as the mechanisms remain unclear. The aim of our study is to explore the impacts of microenergy acoustic pulse (MAP) therapy on urethral and pelvic floor muscle structure and function in female lean and fatty rats.

Methods: A total 24 Zucker fatty (ZF) and 24 Zucker lean (ZL) female 24-week-old rats were grouped into four groups: ZL control, ZLMAP, ZF control, and ZFMAP. For MAP treatment, 500 pulses were delivered at an energy level of 0.033 mJ/mm and a frequency of 3 Hz and were applied twice a week for 4 weeks. After a 1-week washout, all rats underwent conscious cystometry and leak-point pressure (LPP) measurements followed by ex vivo organ-bath assay and histological study.

Results: ZF rats had lower LPP as compared to ZL rats, and MAP treatment significantly improved LPP in ZF rats (P < .05). Impaired muscle contractile activity (MCA) in organ-bath study was noted in ZF rats. MAP treatment significantly increased MCA in ZF rats (P < .05) and also increased the thickness of the striated muscle layer and the number of neuromuscular junctions (NMJs). In situ, MAP activated muscle satellite cells significantly (P < .05).

Conclusions: Obesity impairs the function of both the urethral sphincter and the pelvic floor and leads to atrophy and distortion of the striated muscle in obese female rats. These issues contribute to OA-SUI. MAP improves continence by stimulating muscle regeneration and nerve innervation as well as by activating satellite cells.
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http://dx.doi.org/10.1002/nau.24160DOI Listing
November 2019

The effects of microenergy acoustic pulses on animal model of obesity-associated stress urinary incontinence. Part 2: In situ activation of pelvic floor and urethral striated muscle progenitor cells.

Neurourol Urodyn 2019 11 27;38(8):2140-2150. Epub 2019 Aug 27.

Knuppe Molecular Urology Laboratory, Department of Urology, School of Medicine, University of California, San Francisco, California.

Aim: To investigate the possibility and mechanism of microenergy acoustic pulses (MAP) for activating tissue resident stem/progenitor cells within pelvic and urethral muscle and possible mechanism.

Methods: The female Zucker Lean and Zucker Fatty rats were randomly divided into four groups: ZL control, ZLMAP, ZF control, and ZFMAP. MAP was applied at 0.033 mJ/mm , 3 Hz for 500 pulses, and the urethra and pelvic floor muscles of each rat was then harvested for cell isolation and flow cytometry assay. Freshly isolated cells were analyzed by flow cytometry for Pax-7, Int-7α, H3P, and EdU expression. Meanwhile, pelvic floor muscle-derived stem cells (MDSCs) were harvested through magnetic-activated cell sorting, MAP was then applied to MDSCs to assess the mechanism of stem cell activation.

Results: Obesity reduced EdU-label-retaining cells and satellite cells in both pelvic floor muscle and urethra, while MAP activated those cells and enhanced cell proliferation, which promoted regeneration of striated muscle cells of the pelvic floor and urethral sphincter. Activation of focal adhesion kinase (FAK)/AMP-activated protein kinase (AMPK) /Wnt/β-catenin signaling pathways by MAP is the potential mechanism.

Conclusions: MAP treatment activated tissue resident stem cells within pelvic floor and urethral muscle in situ via activating FAK-AMPK and Wnt/β-catenin signaling pathway.
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http://dx.doi.org/10.1002/nau.24152DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6801020PMC
November 2019

Stem Cells from a Female Rat Model of Type 2 Diabetes/Obesity and Stress Urinary Incontinence Are Damaged by In Vitro Exposure to its Dyslipidemic Serum, Predicting Inadequate Repair Capacity In Vivo.

Int J Mol Sci 2019 Aug 19;20(16). Epub 2019 Aug 19.

Division of Urology, Department of Surgery, Harbor-UCLA Medical Center and Los Angeles Biomedical Research Institute, Torrance, 90502 CA, USA.

Female stress urinary incontinence (FSUI) is prevalent in women with type 2 diabetes/obesity (T2D/O), and treatment is not optimal. Autograph stem cell therapy surprisingly has poor efficacy. In the male rat model of T2D/O, it was demonstrated that epigenetic changes, triggered by long-term exposure to the dyslipidemic milieu, led to abnormal global transcriptional signatures (GTS) of genes and microRNAs (miR), and impaired the repair capacity of muscle-derived stem cells (MDSC). This was mimicked in vitro by treatment of MDSC with dyslipidemic serum or lipid factors. The current study aimed to predict whether these changes also occur in stem cells from female 12 weeks old T2D/O rats, a model of FSUI. MDSCs from T2D/O (ZF4-SC) and normal female rats (ZL4-SC) were treated in vitro with either dyslipidemic serum (ZFS) from late T2D/O 24 weeks old female Zucker fatty (ZF) rats, or normal serum (ZLS) from 24 weeks old female Zucker lean (ZL) rats, for 4 days and subjected to assays for fat deposition, apoptosis, scratch closing, myostatin, interleukin-6, and miR-GTS. The dyslipidemic ZFS affected both female stem cells more severely than in the male MDSC, with some gender-specific differences in miR-GTS. The changes in miR-GTS and myostatin/interleukin-6 balance may predict in vivo noxious effects of the T2D/O milieu that might impair autograft stem cell (SC) therapy for FSUI, but this requires future studies.
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http://dx.doi.org/10.3390/ijms20164044DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6720976PMC
August 2019

Cellular signaling pathways modulated by low-intensity extracorporeal shock wave therapy.

Int J Impot Res 2019 May 22;31(3):170-176. Epub 2019 Jan 22.

Knuppe Molecular Urology Laboratory, Department of Urology, School of Medicine, University of California, San Francisco, CA, 94143, USA.

Low-intensity extracorporeal shock wave therapy (Li-ESWT) is a form of energy transfer that is of lower intensity (<0.2mJ/mm) relative to traditional Extracorporeal Shock Wave Lithotripsy (ESWL) used for management of urinary stones. At this intensity and at appropriate dosing energy transfer is thought to induce beneficial effects in human tissues. The proposed therapeutic mechanisms of action for Li-ESWT include neovascularization, tissue regeneration, and reduction of inflammation. These effects are thought to be mediated by enhanced expression of vascular endothelial growth factor, endothelial nitric oxide synthase, and proliferating cell nuclear antigen. Upregulation of chemoattractant factors and recruitment/activation of stem/progenitor cells may also play a role. Li-ESWT has been studied for management of musculoskeletal disease, ischemic cardiovascular disorders, Peyronie's Disease, and more recently erectile dysfunction (ED). The underlying mechanism of Li-ESWT for treatment of ED is incompletely understood. We summarize the current evidence basis by which Li-ESWT is thought to enhance penile hemodynamics with an intention of outlining the fundamental mechanisms by which this therapy may help manage ED.
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http://dx.doi.org/10.1038/s41443-019-0113-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6587965PMC
May 2019

Delayed Low-Intensity Extracorporeal Shock Wave Therapy Ameliorates Impaired Penile Hemodynamics in Rats Subjected to Pelvic Neurovascular Injury.

J Sex Med 2019 Jan 1;16(1):17-26. Epub 2018 Dec 1.

Knuppe Molecular Urology Laboratory, Department of Urology, School of Medicine, University of California, San Francisco, CA, USA. Electronic address:

Background: Erectile dysfunction (ED) caused by pelvic neurovascular injury (PNVI) is often refractory to treatment. In many cases, erectogenic therapy is administered in a delayed fashion.

Aim: To evaluate penile hemodynamic effects and histologic changes associated with delayed low-intensity extracorporeal shock wave therapy (Li-ESWT) after PNVI ED in a rat model. We visualized images using immunofluorescence and 3-dimensional imaging of solvent-cleared organs (3DISCO), a novel imaging technique.

Methods: A total of 32 Sprague-Dawley male rats aged 12 weeks were divided equally into 4 groups: sham surgery as normal controls (NC), PNVI controls (PC), PNVI with very-low-energy Li-ESWT (PVL), and PNVI with low-energy Li-ESWT (PL). Bilateral cavernous nerve crush and internal pudendal bundle ligation were performed in the 3 PNVI groups. Li-ESWT was administered twice a week for 4 weeks in the PL and PVL groups starting at 4 weeks after PNVI.

Outcomes: Intracavernous pressure (ICP) studies (normalized to mean arterial pressure [MAP]) were conducted in all subject animals. After testing, tissue was harvested for immunofluorescence staining and 3DISCO analysis.

Results: Mean ICP/MAP was lower in PC animals compared with NC animals (0.37 ± 0.03 vs 0.91 ± 0.03, respectively; P = .001). The ICP/MAP ratio was significantly higher in PVL and PL animals (0.66 ± 0.07 and 0.82 ± 0.05, respectively) compared with PC animals (P = .002 and .001, respectively). Detailed microstructures and trajectories of nerves and vessels were identified with immunofluorescence and 3DISCO. The PC group had lower density of nerves, axons, neuronal nitric oxide synthase-positive nerves, and Schwann cells in the dorsal penis. Animals in the PL group had significantly higher expression of all of these markers compared with PC animals.

Clinical Implications: Li-EWST may have utility in the management of severe ED related to PNVI from severe pelvic injury or radical pelvic surgeries, even when administered in a delayed fashion.

Strength & Limitations: This study of a severe ED phenotype involved treatment administered in a delayed fashion, which is more consistent with how therapy likely would be delivered in a real-world clinical context. Moreover, because the treatment commenced at 4 weeks after injury, when nerve and tissue atrophy have already occurred, the results imply that Li-ESWT can be used for regenerative therapy. Additional studies on dose optimization and treatment interval are needed to inform the design of human clinical trials.

Conclusion: Li-ESWT ameliorates the negative functional and histologic effects of severe pelvic neurovascular injury in a rat model system. 3DISCO provides high-resolution images of neuroanatomy and neural regeneration. Wang HS, Ruan Y, Banie L, et al. Delayed Low-Intensity Extracorporeal Shock Wave Therapy Ameliorates Impaired Penile Hemodynamics in Rats Subjected to Pelvic Neurovascular Injury. J Sex Med 2019;16:17-26.
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http://dx.doi.org/10.1016/j.jsxm.2018.11.003DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6326879PMC
January 2019

Long-term therapeutic effect of cell therapy on improvement in erectile function in a rat model with pelvic neurovascular injury.

BJU Int 2019 07 27;124(1):145-154. Epub 2019 Feb 27.

Wake Forest Institute for Regenerative Medicine, Wake Forest School of Medicine, Winston-Salem, NC, USA.

Objective: To determine the long-term therapeutic effect amongst three human cell types on erectile function recovery in a rat model of dual neurovascular-injury erectile dysfunction (NVED).

Materials And Methods: A dual NVED model was established in athymic rats by crushing the bilateral cavernous nerves and ligating the bilateral internal pudendal neurovascular bundles. At the time of defect creation, three different types of human cell populations (2.5 × 10  cells/0.2 mL: umbilical vein endothelial cells, adipose-derived stem cells, and amniotic fluid-derived stem cells) were injected intracavernously into the penile tissue. Saline injection (0.2 mL) served as a control group. Erectile function and histomorphological analyses of penile tissues were assessed 12 weeks after defect creation and cell or saline injection.

Results: The ratio of intracavernous pressure to mean arterial pressure (functional indicator) was significantly higher in the cell therapy groups compared to the saline-injected control group (P < 0.05). Immunofluorescence staining showed more cells expressing biomarkers of endothelial, smooth muscle, and nerve cells within the penile tissue in the cell therapy groups when compared to the control group.

Conclusions: Cell therapy enhanced erectile function and ameliorated the histological changes 12 weeks after pelvic neurovascular injury in vivo, indicating that cell therapy may improve the long-term outcomes in neurogenic, myogenic and vascular tissue regeneration in the treatment of NVED.
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http://dx.doi.org/10.1111/bju.14631DOI Listing
July 2019

Randomized study of percutaneous ureteroscopic plasma column electrode decortication and laparoscopic decortication in managing simple renal cyst.

Transl Androl Urol 2018 Apr;7(2):260-265

Department of Urology, School of Medicine, University of California, San Francisco, CA, USA.

Background: To assess the safety and efficacy of a novel technology referred to as percutaneous ureteroscopic plasma column electrode (PCE) by comparing laparoscopic decortication in the management of simple renal cyst (SRC).

Methods: Between March 2016 and June 2017, 53 patients with SRCs were randomized to divided into two groups, the PCE group (24 patients), or laparoscope group (29 patients). The operative time, blood loss, days of drainage, catheter, and hospital stay and complications were compared with the two groups. All patients were followed- up to 6 months after treatment.

Results: No patients had intraoperative complications such as hemopneumothorax, adjacent organ injury, infection or hemorrhage shock. In the PCE group and laparoscope group: the mean operation time was 34.1±8.2 58.4±16.7 min (P<0.05). The mean blood loss was 2.0±1.16 9.7±4.09 mL (P<0.05). The mean postoperative indwelling drainage tube time was 2.5±1.5 2.9±1.09 d (P>0.05). The mean intra-urethral indwelling catheter time was 2.1±0.88 2.0±1.15 d (P>0.05). The mean postoperative hospital stay was 3.0±1.7 3.7±1.53 (P>0.05). One patient in electrode group was suffered from rupture of the collecting system during the operation, and was treated by indwelling D-J stent. During follow up, no cysts recurrence was found.

Conclusions: Percutaneous ureteroscopic PCE decortication is a safe, minimally invasive and effective therapy to treat SRCs, with equal efficacy and advantages in shortening the operation time and reducing the amount of intraoperative bleeding compared with laparoscopic decortication.
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http://dx.doi.org/10.21037/tau.2018.03.08DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5911539PMC
April 2018

Treatment of stress urinary incontinence with low-intensity extracorporeal shock wave therapy in a vaginal balloon dilation induced rat model.

Transl Androl Urol 2018 Mar;7(Suppl 1):S7-S16

Knuppe Molecular Urology Laboratory, Department of Urology, School of Medicine, University of California, San Francisco, CA, USA.

Background: To investigate the outcomes and mechanisms of low-intensity extracorporeal shock wave therapy (Li-ESWT) on stress urinary incontinence (SUI) in a vaginal balloon dilation (VBD) rat model.

Methods: Thirty Sprague-Dawley rats were randomly grouped into normal controls, VBD only, and VBD with Li-ESWT. Li-ESWT was administered twice per week for 3 weeks. Afterward, all 30 rats were assessed with functional and histological studies. To explore the acute effect of Li-ESWT, another 25 rats, given intraperitoneal 5-ethynyl-2-deoxyuridine (EdU) at birth, were treated with Li-ESWT followed by assessment of vascular endothelial growth factor (VEGF) expression and endogenous progenitor cells distribution at 24 hours or 1 week after the last Li-ESWT therapy. Additionally, rat myoblast L6 cells were used for myotube formation assay .

Results: Functional analysis with leak-point pressure (LPP) testing showed that rats treated with Li-ESWT following VBD had significantly higher LPP relative to those receiving VBD only (44.8±3.2 versus 27.0±2.9 cmHO, P<0.01). Histological examinations showed increased urethral sphincter regeneration in Li-ESWT group. The rats treated with Li-ESWT also had increased vascularity, which was confirmed by immunohistochemistry of rat endothelial cell antigen, while reverse-transcriptase polymerase chain reaction (RT-PCR) showed VEGF expression was significantly enhanced. Additionally, there were significantly increased EdU+ cells in Li-ESWT treated rats at 24 hours. , Li-ESWT promoted myotube formation from L6 cells.

Conclusions: Li-ESWT ameliorated SUI by promoting angiogenesis, progenitor cell recruitment, and urethral sphincter regeneration in a rat model induced by VBD. Li-ESWT represents a potential novel non-invasive therapy for SUI.
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http://dx.doi.org/10.21037/tau.2017.12.36DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5881209PMC
March 2018

Low-intensity extracorporeal shockwave therapy ameliorates diabetic underactive bladder in streptozotocin-induced diabetic rats.

BJU Int 2018 09 20;122(3):490-500. Epub 2018 Apr 20.

Knuppe Molecular Urology Laboratory, Department of Urology, School of Medicine, University of California, San Francisco, CA, USA.

Objectives: To evaluate the therapeutic effect of once-weekly low-intensity extracorporeal shock wave therapy (Li-ESWT) on underactive bladder (UAB) in the streptozotocin (STZ)-induced diabetic rat model.

Materials And Methods: In all, 36 female Sprague-Dawley rats were divided into three groups: normal control (NC), diabetes mellitus control (DMC), and DM with Li-ESWT (DM Li-ESWT). The two DM groups received an intraperitoneal 60 mg/kg STZ injection to induce DM. The Li-ESWT was applied toward the pelvis of the rats starting 4 weeks after STZ administration and lasting for 4 weeks. The Li-ESWT was given once weekly, with an energy flux density of 0.02 mJ/mm at 3 Hz for 400 pulses. All rats underwent conscious cystometry, leak-point pressure (LPP) assessment, ex vivo organ-bath study, histology, immunofluorescence, and Western Blot analysis.

Results: Conscious cystometry revealed voiding dysfunction in the DMC group, whereas the DM Li-ESWT group showed significantly improved voiding function, reflected in a reduced post-void residual urine volume and increased LPP compared to the DMC group. Ex vivo organ-bath studies showed that Li-ESWT enhanced muscle contractile activity of the bladder and urethra during electrical-field stimulation and drug stimulation. Histologically, Li-ESWT significantly restored bladder morphology, reflected by a reduction in the intravesical lumen area and increased muscle proportion of the bladder wall. Western Blot analysis showed higher smooth muscle actin expression in the bladder wall in the DM Li-ESWT group compared to the DMC group. Immunofluorescence showed decreased nerve-ending distribution, and destroyed and shortened nerve fibres in the DMC group, and recovery of neuronal integrity and innervation in the DM Li-ESWT group.

Conclusions: In conclusion, Li-ESWT ameliorated UAB and urinary incontinence in the diabetic UAB rat model. The improvement appears to be the result of restoration of bladder and urethral structure and function by Li-ESWT. Li-ESWT is non-invasive and may become a better alternative therapy for UAB. Further investigations are warranted.
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http://dx.doi.org/10.1111/bju.14216DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6158099PMC
September 2018
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