Tyrosine Kinase Inhibitors Diminish Renal Neoplasms in a Tuberous Sclerosis Model Via Induction of Apoptosis.

Tuberous sclerosis complex (TSC) tumors are presently incurable despite a cytostatic response to mTOR pathway inhibition because recurrence of disease occurs after treatment is discontinued. Here, we explored the hypothesis that inhibiting tyrosine kinase activity in mesenchymal lineage-specific platelet-derived growth factor receptor ß (PDGFRß) signaling in TSC tumors is cytocidal and attenuates tumorigenesis at significantly higher levels than treatment with an mTOR inhibitor. Rapamycin-induced versus tyrosine kinase inhibitor (TKI)-induced renal angiomyolipoma (AML) and pulmonary lymphangioleiomyomatosis (LAM) tumor cells were comparatively analyzed using cell survival assays, RNA sequencing, and bioinformatics to distinguish tumoricidal mechanisms adopted by each drug type. The efficacy of imatinib therapy was validated against spontaneously developing renal cystadenomas in tuberous sclerosis Tsc2+/- mouse models (C57BL/6J mice; N = 6; 400 mg/kg/d; oral gavage) compared with Tsc2+/- mice treated with PBS (C57BL/6J mice; N = 6). Our study revealed that TKIs imatinib and nilotinib were cytocidal to both pulmonary LAM and renal AML cell cultures through the downregulation of the glycoprotein GPVI pathway and resultant disruption in mitochondrial permeability, increased cytosolic cytochrome C, and caspase 3 activation. Importantly, renal tumor growth was significantly attenuated in imatinib-treated Tsc2+/- mice compared with PBS treatment. The preclinical studies reported here provide evidence documenting the effectiveness of TKIs in limiting LAM and AML cell growth and viability with important clinical potential. Furthermore, these drugs elicit their effects by targeting a PDGF pathway-dependent apoptotic mechanism supporting the investigation of these drugs as a novel class of TSC therapeutics.

Asa G Yancey: The first to describe a modification of the Swenson Technique for Hirschsprung disease.

Hirschsprung disease is a common disease treated by surgeons using different approaches. One approach is eponymously ascribed to Franco Soave and Scott Boley involving a pull-through of ganglionated colon through a distal portion of aganglionated rectum. However, more recent evidence has shown that this same technique was described twelve years before by Asa Yancey, a black surgeon. A review of the evidence follows with a focus on why Yancey may not have rightly received the credit that was because of him.

Athletic Hip Injuries in Major League Baseball Pitchers Associated With Ulnar Collateral Ligament Tears.

BACKGROUND: Ulnar collateral ligament (UCL) reconstruction is a reliable treatment for elite overhand throwers with UCL tears. In recent years, this procedure has become increasingly common among Major League Baseball (MLB) pitchers. Predisposing factors and associated comorbidities, however, have not been fully elucidated. PURPOSE/HYPOTHESIS: The purpose of this study was to determine whether professional baseball pitchers who underwent UCL reconstruction had an increased incidence of hip or groin injuries 4 years before or after surgery. We hypothesized that MLB pitchers who sustain hip or groin injuries may be more likely to develop UCL tears because of alterations and overcompensation in the kinetic chain during overhand throwing. STUDY DESIGN: Cohort study; Level of evidence, 3. METHODS: A comprehensive list of all 247 MLB players who underwent UCL reconstruction between 2005 and 2017 was created using publicly accessible online data. The application of inclusion criteria yielded a final sample size of 145 athletes. These athletes' injury histories were identified and cross-referenced with the official MLB disabled list. Matched controls were generated for a comparison of results. RESULTS: Of the 145 MLB pitchers who underwent UCL reconstruction between 2005 and 2017, 40 (27.6%) endured a proximal lower extremity injury within 4 years of their surgery. Specifically, 16 pitchers sustained hip injuries, 13 suffered hamstring injuries, and 14 experienced groin injuries. A significantly lower rate of hip- and groin-related injuries (17.9%) was identified in matched controls during a similar time frame (P = .049). CONCLUSION: The results of this study demonstrate that MLB pitchers who required UCL reconstruction sustained a higher frequency of proximal lower extremity injuries both before and after surgery compared with matched controls. This finding is significant as the treatment of antecedent hip lesions, as well as an emphasis on hip and core muscle mobility and strengthening, may help reduce injuries to the UCL.

Professional Athletes' Return to Play and Performance After Operative Repair of an Achilles Tendon Rupture.

BACKGROUND: Most Achilles tendon ruptures are sports related. However, few studies have examined and compared the effect of surgical repair for complete ruptures on return to play (RTP), play time, and performance across multiple sports. PURPOSE: To examine RTP and performance among professional athletes after Achilles tendon repair and compare pre- versus postoperative functional outcomes of professional athletes from different major leagues in the United States. STUDY DESIGN: Cohort study; Level of evidence, 3. METHODS: National Basketball Association (NBA), National Football League (NFL), Major League Baseball (MLB), and National Hockey League (NHL) athletes who sustained a primary complete Achilles tendon rupture treated surgically between 1989 and 2013 were identified via public injury reports and press releases. Demographic information and performance-related statistics were recorded for 2 seasons before and after surgery and compared with matched controls. Statistical analyses were used to assess differences in recorded metrics. RESULTS: Of 86 athletes screened, 62 met inclusion criteria including 25 NBA, 32 NFL, and 5 MLB players. Nineteen (30.6%) professional athletes with an isolated Achilles tendon rupture treated surgically were unable to return to play. Among athletes who successfully returned to play, game participation averaged 75.4% ( P < .001) and 81.9% ( P = .002) of the total games played the season before injury at 1 and 2 years postoperatively, respectively. Play time was significantly decreased and athletes performed significantly worse compared with preoperative levels at 1 and 2 years after injury ( P < .001). When players were compared with matched controls, an Achilles tendon rupture resulted in fewer games played ( P < .001), decreased play time ( P = .025), and worse performance statistics ( P < .001) at 1 year but not 2 years postoperatively ( P > .05). When individual sports were compared, NBA players were most significantly affected, experiencing significant decreases in games played, play time, and performance. CONCLUSION: An Achilles tendon rupture is a devastating injury that prevents RTP for 30.6% of professional players. Athletes who do return play in fewer games, have less play time, and perform at a lower level than their preinjury status. However, these functional deficits are seen only at 1 year after surgery compared with matched controls, such that players who return to play can expect to perform at a level commensurate with uninjured controls 2 years postoperatively.

Collagenolytic matrix metalloproteinases in chronic obstructive lung disease and cancer.

Chronic obstructive pulmonary disease (COPD) and lung cancer result in significant morbidity and mortality worldwide. In addition to the role of environmental smoke exposure in the development of both diseases, recent epidemiological studies suggests a connection between the development of COPD and lung cancer. Furthermore, individuals with concomitant COPD and cancer have a poor prognosis when compared with individuals with lung cancer alone. The modulation of molecular pathways activated during emphysema likely lead to an increased susceptibility to lung tumor growth and metastasis. This review summarizes what is known in the literature examining the molecular pathways affecting matrix metalloproteinases (MMPs) in this process as well as external factors such as smoke exposure that have an impact on tumor growth and metastasis. Increased expression of MMPs provides a unifying link between lung cancer and COPD.

Influence of berry polyphenols on receptor signaling and cell-death pathways: implications for breast cancer prevention.

Breast cancer is the most commonly diagnosed cancer among women worldwide. Many women have become more aware of the benefits of increasing fruit consumption, as part of a healthy lifestyle, for the prevention of cancer. The mechanisms by which fruits, including berries, prevent breast cancer can be partially explained by exploring their interactions with pathways known to influence cell proliferation and evasion of cell-death. Two receptor pathways, estrogen receptor (ER) and tyrosine kinase receptors, especially the epidermal growth factor receptor (EGFR) family, are drivers of cell proliferation and play a significant role in the development of both primary and recurrent breast cancer. There is strong evidence to show that several phytochemicals present in berries such as cyanidin, delphinidin, quercetin, kaempferol, ellagic acid, resveratrol, and pterostilbene interact with and alter the effects of these pathways. Furthermore, they also induce cell death (apoptosis and autophagy) via their influence on kinase signaling. This review summarizes in vitro data regarding the interaction of berry polyphenols with the specific receptors and the mechanisms by which they induce cell death. This paper also presents in vivo data of primary breast cancer prevention by individual compounds and whole berries. Finally, a possible role for berries and berry compounds in the prevention of breast cancer and a perspective on the areas that require further research are presented.

Effect of Berry Extracts and Bioactive Compounds on Fulvestrant (ICI 182,780) Sensitive and Resistant Cell Lines.

Fulvestrant (ICI 182,780; ICI) is approved for the treatment of advanced metastatic breast cancer that is unresponsive to other endocrine therapies. Berries are frequently consumed for their antioxidant, anti-inflammatory, and anticancer potential. In this study, we tested the efficacy of two berry extracts (Jamun-EJAE and red raspberry-RRE) and their bioactive compounds (Delphinidin-Del and Ellagic acid-EA) to inhibit cell proliferation with or without a sublethal dose of ICI in various breast cancer cell lines. ICI-sensitive (LCC1, ZR75-1, and BT474) and -resistant (LCC9, ZR75-1R) cells were subjected to treatment with berry extracts alone (0.1-100 µg/mL) or with a sub-lethal dose of ICI ( 1). EA, in doses tested, did not have any significant effects on any of the cell lines. Finally, we found that the extracts were more effective at lower, physiologically relevant concentrations than at higher experimental doses.