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Efficacy of PARP Inhibitors as Maintenance Therapy for Metastatic Castration-Resistant Prostate Cancer: A Meta-Analysis of Randomized Controlled…

Posted: November 21, 2021 at 9:42 pm

Introduction

Prostate cancer is the second most common and fifth most aggressive cancer among men worldwide.1 According to one estimate, 1 in 7 US men and 1 in 25 men worldwide will be diagnosed with prostate cancer during his lifetime.1 Despite the advanced screening methods available, such as measurement of prostate-specific antigen levels, the incidence of metastatic disease remains as high as 20%.2 The best-known risk factors for prostate cancer are race (ie, African American descent), obesity, and genetics (eg, BRCA1/2 mutations). Gleason scoring is commonly used for histopathologic evaluation and for clinical and pathologic staging of disease. Patients with high-risk disease are treated with prostatectomy and/or external beam radiotherapy followed by androgen deprivation therapy (ADT) as maintenance therapy. If disease progression occurs while the patient is receiving ADT, the disease is noted to be castration-resistant prostate cancer (CRPC). Unfortunately, the majority of patients with prostate cancer progress to castration-resistant disease within 2 to 3 years.3

For decades the standard-of-care (SOC) treatment for metastatic CRPC (mCRPC) has been composed of cytotoxic agents, including taxanes (docetaxel or cabazitaxel [Jevtana]), and second-generation antihormonal agents (antihormonal therapy; AHT) such as abiraterone (Zytiga) or enzalutamide (Xtandi). Previously, CRPC was called androgen-independent prostate cancer and hormone-refractory prostate cancer.4 Subsequently, results of several studies showed that intratumoral (intracrine and paracrine) androgen production plays a significant role in the development of resistance among prostate cancer cells to testosterone suppression therapy.5

Other treatment options include pembrolizumab (Keytruda) for PD-L1positive and microsatellite instability (MSI)high disease, and radium-223 (Xofigo) for bone metastasis. PARP1 (or PARP) inhibitors are used in patients with mutations in homologous recombination repair (HRR) genes (most commonly, BRCA1/2). Recent study results indicate that the androgen receptor (AR) regulates the DNA repair pathways, and reciprocally, several enzymes involved in DNA repair can moderate AR activity.6-8 An example of such an enzyme is PARP1, which is involved in identifying single-stranded DNA breaks and their repair through the base excision method.9 Several cancers, including prostate cancer, exhibit increased PARP1 activity or expression.9-11 The mechanism of action of PARP inhibitors includes physical obstruction of the replication fork (PARP trapping), which affects HRR, resulting in DNA double-strand breaks.12 Previous study results have shown that these PARP inhibitors are synergistic when used with agents affecting the AR pathway regardless of HRR mutation status.9,13 In 2020, for the first time, the FDA approved PARP inhibitors for use in mCRPC.

The aim of this meta-analysis is to analyze the efficacy of these drugs in the treatment of mCRPC in terms of progression-free survival (PFS) and overall survival (OS), using the results of completed trials.

The authors followed PRISMA guidelines.

The databases accessed were Cochrane Central Registry of Clinical Trials, Embase, and PubMed. Search terms used were PARP inhibitors, prostate cancer, prostate neoplasm, olaparib (Lynparza), veliparib.

Papers had no restrictions in terms of date or status ofpublications. To be included, however, the papers had to report on RCTs that:

1. compared PARP inhibitors against SOC in patients with mCRPC;

2. reported PFS and OS;

3. included only patients 18 years or older; and

4. were available in the English language.

Papers that did not meet the above criteria were excluded.

Three authors independently reviewed all articles and abstracts and excluded the irrelevant trials. Risk of bias for selected papers was assessed using the Cochrane Collaboration tool and then classified as high, uncertain, or low.

Information was extracted using a prespecified extraction table. Information was extracted from the papers by reading through the main texts and tables, and a second author reviewed the information collected to ensure its accuracy. The extracted data included HRs for PFS and OS.

The meta-analysis was performed using Comprehensive Meta-analysis software version 3. HRs were calculated for PFS and OS . For effect sizes, a 95% CI was used, and a P value of less than .05 indicated statistical significance. Analysis was done using random and fixed models and both were reported. Heterogeneity was evaluated using I2 statistic and categorized as low (<40), moderate (40-60), and high (>60). Where a median was used, it was assumed to be equivalent to the mean, and SDs were estimated by dividing interquartile differences by 1.35. Fixed effectanalysis is usually adapted in cases where I2 value is 50%; otherwise, random effect model is used.

The initial search identified 351 articles; removal of duplicates left 322. The first screening excluded 262 articles. The full texts of the remaining 60 articles were analyzed. Thirty-seven articles were excluded because the trials described were incomplete; 13 were review articles; 2 described trials that were terminated; 4 were about single-arm studies; and 1 articles study did not have relevant intervention. Ultimately, articles describing 3 RCTs were included, and these trials had a total of 682 patients. The PRISMA flow diagram is shown in Figure 1, and main characteristics of RCTs are listed in the Table.

Risk of bias

The results of risk of bias are shown in Figure 2 and Figure 3.

Overall survival

Two studies reported OS when patients usedPARP inhibitors compared with SOC.14,15 The difference was statistically significant when calculated using the fixed model (HR, 0.751; 95% CI, 5.82-0.968; P = .027), and I2 = 23.23. When calculated using the random model, there was a strong deviation favoringPARP inhibitors,but it did not reach statistical significance (HR, 0.758; 95% CI, 0.565-1.017; P = .064)(Figure 4).

Progression-free survival

Three studies reported PFS when patients usedPARP inhibitorscompared with SOC.14-16 The difference was statistically significant when calculated using the fixed model (HR, 0.626; 95% CI, 0.521-0.752; P <.001), and I2 = 80.240. When calculated using the random model, there was a strong deviation favoringPARP inhibitors, but it did not reach statistical significance (HR, 0.674; 95% CI, 0.437-1.039; P = .074)(Figure 5).

Overall results of this meta-analysis indicate that patients with mCRPC experience survival benefits when treated with PARP inhibitors as compared with placebo or SOC chemotherapy. OS was better in the PARP inhibitor group under fixed effect (HR, 0.751; 95% CI,0.582-0.968; P = .027) and under random effect (HR, 0.758; 95% CI, 0.565-1.017; P = .064). PFS was improved in the PARP inhibitor group (HR, 0.626; 95% CI, 0.521-0.752; P <.001) compared with the chemotherapy group when analyzed under fixed effect.

In 2020, the FDA approved 2 PARP inhibitorsrucaparib (Rubraca) and olaparibto treat mCRPC in patients harboring somatic and/or germline mutations in BRCA1 or BRCA2 as well as in ATM genes. This decision was based upon the data from the multicenter, single-arm TRITON2 clinical trial (NCT02952534), in which rucaparib was used in patients with mCRPC positive for BRCA mutations. Currently, numerous clinical trials are ongoing to determine the efficacy of PARP inhibitors in mCRPC. Ongoing clinical trials with olaparib, veliparib, rucaparib, niraparib (Zejula), and talazoparib (Talzenna) in mCRPC were searched on the clinicaltrials.gov website. Currently, 37 trials are ongoing, 2 have been terminated, and 3 trials have been completed.

In 2 trials, olaparib was the study drug.14,15 In Clarke et al, patients were randomized into the treatment group (abiraterone plus olaparib) or the control group (abiraterone alone) irrespective of any genetic mutations or biomarker criteria. The study showed statistically significant improvement in both PFS and OS in the treatment group, indicating that a broader population, regardless of HRR mutation status, can benefit from the synergy of PARP inhibitors and AR inhibitors. However, men with HRR mutations derive the greatest benefit from these medications.

Our literature review also shows that PARP inhibitors are much more effective in patients with HRR or ATM mutations. In the PROfound study (NCT02987543; de Bono et al), patients were divided into 2 cohorts: Cohort A included patients with 1 or more of 3 mutations (BRCA1/2; ATM), and Cohort B included patients with a mutation in any of 12 other prespecified genes. Each cohort was divided into a treatment arm (olaparib) and a control arm (enzalutamide or abiraterone). OS was prolonged when measured together for cohorts A and B: 17.5 months with PARP inhibitor vs 14.4 months with chemotherapy (HR for death, 0.67; 95% CI, 0.49-0.93). The PFS for cohort A vs cohort B was 7.4 months vs 3.6 months, respectively; HR for progression or death, 0.34; 95% CI, 0.25-0.47; P < .001. The results for Cohort A and B combined showed median PFS to be 5.8 months vs 3.5 months (HR, 0.49; 95% CI, 0.38-0.63; P <.001). Once again, these results indicate that PARP inhibitors are effective in patients with mCRPC regardless of genetic mutation status, although responses are much more evident in the population with BRCA and ATM alterations.

In the third trial (NCT01576172; Hussain et al), veliparib was compared with a control regimen of abiraterone plus prednisone.16 The investigators primary objective was to see if ETS fusion status (related to a family of transcription factors) has a role in the tumor response to the treatment. Patients were first divided according to ETS fusion status (positive or negative) and then equally distributed in the case and control cohorts. Surprisingly, there was no difference in PFS between the treatment arms, regardless of ETS status, with overall PFS of 11 months (95% CI, 8.1-13.6) in the treatment group vs 10.1 months (95% CI, 8.2-13.8) in the control group (P = .99). However, a significant finding was that DNA repair status (ie, DRD gene mutation) was associated with statistically significant improvement in PFS regardless of treatment status: 14.5 months (abnormal DRD gene) vs 8 months (normal DRD gene) (HR, 0.52; 95% CI, 0.29-0.93; P = .02). This study was not included in the forest plot for OS because OS was not calculated in this group.

This study, as a meta-analysis, remains a retrospective chart review; the possibility for biases exists. Fewer trials and smaller study populations lead to publication bias. We made our best effort to locate all relevant published studies, randomize them, and complete data extraction and analysis. Another major limitation of this trial is the difficulty in performing stratified pool analysis for each PARP inhibitor drug; only a very limited number of completed phase 2/3 RCTs have currently available results. Other potential contributors to bias for this meta-analysis include heterogeneous population and inclusion criteria (with different first-line therapy patients and BRCA or other gene mutations). Another limitation is the inability to compare the adverse effect profiles between the PARP inhibitor and chemotherapy groups.

Conversely, a strength of this analysis is that it includes all phase 2/3 RCTs evaluating the efficacy of PARP inhibitors in mCRPC that have been completed and published, to date.

This meta-analysis shows that PARP inhibitors can prolong PFS or OS compared to SOC treatment in patients with mCRPC irrespective of HRR or other genetic mutation status. Longer PFS and OS were seen when PARP inhibitors were used alone or in combination with AHT therapies like abiraterone or enzalutamide. The effect was more significant when examined with a fixed model analysis. Although there was a significant deviation towards an increase in PFS and OS in the random model analysis, the effect was not statistically significant, and it was likely secondary to a relatively small patient population in the meta-analysis. Although, at baseline, there was heterogeneity among the populations participating in these trials, in terms of genetic alterations, the results of all the trials showed better outcomes in their intervention arms. This heterogeneity can be dealt with by incorporating more RCTs into meta-analyses going forward. More studies can further magnify these results once they are published.

DECLARATIONS

Ethics Approval and Consent to Participate: The data extracted and manuscript were reviewed with the Research Department and Ethics Committee of Department of Medicine, Staten Island University Hospital/Northwell. No experimental intervention was performed, and no specifications of guidelines, legislations, or permissions were required.

Availability of data and materials: Data are available in Excel files. Patient identifying information was removed at all stages in all the studies included.

Competing interests: No competing financial or personal interests are involved for all the authors.

Funding: No funding was obtained from any organization or personnel during any stage of manuscript writing or submission.

Authors contributions: Manuscript written and data obtained by M.R.K.N, A.J, S.S, S.B.S. Proofreading and literature review done by D.A and A.B.

AUTHOR AFFILIATIONS:

1. Department of Internal Medicine, Zucker School of Medicine at Hofstra/Northwell at Staten Island University Hospital, Staten Island, NY, USA.

2. Division of Hematology and Medical Oncology, Zucker School of Medicine at Hofstra/Northwell at Staten Island University Hospital, Staten Island, NY, USA.

1. Barsouk A, Padala SA, Vakiti A, et al. Epidemiology, staging and management of prostate cancer. Med Sci (Basel). 2020;8(3):28. doi:10.3390/medsci8030028

2. Studer UE, Hauri D, Hanselmann S, et al. Immediate versus deferred hormonal treatment for patients with prostate cancer who are not suitable for curative local treatment: results of the randomized trial SAKK 08/88. J Clin Oncol. 2004;22(20):4109-4118. doi:10.1200/jco.2004.11.514

3. Harris WP, Mostaghel EA, Nelson PS, Montgomery B. Androgen deprivation therapy: progress in understanding mechanisms of resistance and optimizing androgen depletion. Nat Clin Pract Urol. 2009;6(2):76-85. doi:10.1038/ncpuro1296

4. Ahmad K. New progress in treatment of hormone-refractory prostate cancer. Lancet Oncol. 2004;5(12):706. doi:10.1016/s1470-2045(04)01641-9

5. Montgomery RB, Mostaghel EA, Vessella R, et al. Maintenance of intratumoral androgens in metastatic prostate cancer: a mechanism for castration-resistant tumor growth. Cancer Res. 2008;68(11):4447-4454. doi:10.1158/0008-5472.Can-08-0249

6. Haffner MC, Aryee MJ, Toubaji A, et al. Androgen-induced TOP2B-mediated double-strand breaks and prostate cancer gene rearrangements. Nat Genet. 2010;42(8):668-675. doi:10.1038/ng.613

7. Schiewer MJ, Knudsen KE. Linking DNA damage and hormone signaling pathways in cancer. Trends Endocrinol Metab. 2016;27(4):216-225 .doi:10.1016/j.tem.2016.02.004

8. Ta HQ, Gioeli D. The convergence of DNA damage checkpoint pathways and androgen receptor signaling in prostate cancer. Endocr Relat Cancer. 2014;21(5):R395-R407. doi:10.1530/erc-14-0217

9. Schiewer MJ, Goodwin JF, Han S, et al. Dual roles of PARP-1 promote cancer growth and progression. Cancer Discov. 2012;2(12):1134-1149. doi:10.1158/2159-8290.Cd-12-0120

10. Hirai K, Ueda K, Hayaishi O. Aberration of poly(adenosine diphosphate-ribose) metabolism in human colon adenomatous polyps and cancers. Cancer Res. 1983;43(7):3441-3446.

11. Fukushima M, Kuzuya K, Ota K, Ikai K. Poly(ADP-ribose) synthesis in human cervical cancer cell -diagnostic cytological usefulness. Cancer Lett. 1981;14(3):227-236. doi:10.1016/0304-3835(81)90148-8

12. OConnor MJ. Targeting the DNA damage response in cancer. Mol Cell. 2015;60(4):547-560. doi:10.1016/j.molcel.2015.10.040

13. Asim M, Tarish F, Zecchini HI, et al. Synthetic lethality between androgen receptor signalling and the PARP pathway in prostate cancer. Nat Commun. 2017;8(1):374. doi:10.1038/s41467-017-00393-y

14. de Bono J, Mateo J, Fizazi K, et al. Olaparib for metastatic castration-resistant prostate cancer. N Engl J Med. 2020;382(22):2091-2102. doi:10.1056/NEJMoa1911440

15. Clarke N, Wiechno P, Alekseev B, et al. Olaparib combined with abiraterone in patients with metastatic castration-resistant prostate cancer: a randomised, double-blind, placebo-controlled, phase 2 trial. Lancet Oncol. 2018;19(7):975-986. doi:10.1016/s1470-2045(18)30365-6

16. Hussain M, Daignault-Newton S, Twardowski PW, et al. Targeting androgen receptor and DNA repair in metastatic castration-resistant prostate cancer: results from NCI 9012. J Clin Oncol. 2018;36(10):991-999. doi:10.1200/jco.2017.75.7310

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Efficacy of PARP Inhibitors as Maintenance Therapy for Metastatic Castration-Resistant Prostate Cancer: A Meta-Analysis of Randomized Controlled...

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Arizona Cardinals at Seattle Seahawks (2021): Game time, TV schedule, and how to watch online – Revenge of the Birds

Posted: at 9:38 pm

It is a big one for both sides.

The Cardinals can basically eliminate the Seahawks from NFC West contention and all but close their already small playoff chances.

Meanwhile, the Seahawks have to find a way to stay alive, that is all they have left right now.

Here is everything you need to know about the game.

Who: Arizona Cardinals (8-2) vs Seattle Seahawks (3-6)

Where: Lumen Field, Seattle, WA

When: November 21, 2021 - 2:25 p.m. Arizona Time

TV: Fox (Channel 10 Locally) - Kenny Albert (play-by-play) Jonathan Vilma (analyst) Sara Walsh (sideline reporter)

Streaming: Fubo TV

Local Radio: Arizona Sports 98.7 FM - Dave Pasch (play-by-play) Ron Wolfley (analyst) and Paul Calvisi (sideline)

Spanish Radio: KHOV 105,1 FM - Luis Hernandez (Play-by-Play) Rolando Cantu (Color Analyst)

National Radio: ESPN Radio - Roxy Bernstein (play-by-play) Kelly Stouffer (analyst) Jessamyn McIntyre (sideline reporter)

Odds: Cardinals -1.5Over/Under: 47.5DraftKings Sportsbook

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Senators Rand Paul and Bernie Sanders work together to block arms sale in Saudi Arabia – Eyewitness News (WEHT/WTVW)

Posted: at 9:38 pm

Senators Rand Paul and Bernie Sanders work together to block arms sale in Saudi Arabia

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Fatal accident in Owensboro leaves motorcyclist dead

Man sets house on fire after barricading himself

End of an era in Evansville: City says goodbye to 420 Main building

Implosion of 420 Main building

Home Team Friday: Gibson Southern vs. Tri-West (11/20/21)

Home Team Friday: Mt. Carmel vs Tolono Unity (11/20/21)

Cody's Detailed Forecast November 20, 2021

City prepares to say goodbye to 420 Main building

Brad Byrd inDEPTH: Implosion preparations for 420 Main

Getting ready for the big day: contractors, police share details ahead of 420 Main implosion

Mayor Winnecke and Wayne Hart discuss Homeless Experience Project

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Keith Allison of Paul Revere and the Raiders Dies – Ultimate Classic Rock

Posted: at 9:38 pm

Former Paul Revere and the Raiders singer/guitarist Keith Allison has died. He also worked with Ringo Starr, the Monkees and the Beach Boys over the years.

It is with deep sadness [we] announce the passing of Keith Allison, Paul Revere and the Raiders said in an official statement. We all here in the Raider family are terribly heartbroken. Keith will always be a Raider. Our love goes out to Keiths wife Tina, son Ryeland, daughters Allison and Brenda, and all the grandchildren. Keith was a friend to all, and everyone loved Keith. His presence will be strongly missed.

Allison had been associated with the group for several years before somewhat reluctantly joining in 1968. He came to their attention after being hired as a permanent audience member for Dick Clarks TV show Where the Action Is, as a result of bearing a resemblance to Paul McCartney.

I'd just signed a recording deal with Warner Bros., and I just signed a solo contract with Dick Clark Productions, Allison later told Classic Bands. I felt it would be like kicking Dick Clark in the shins. I thought that would have been bad karma.

Allison light-heartedly described his decision to finally become a member of the Raiders as a step sideways. I was doing the same thing I always did. I traveled with them everywhere. I toured with them all the time. We were on the TV show together," he said. I was so closely associated with them that it wasn't that big of a jump one way or the other, because of the TV show. I had played on a lot of their records, played guitar on 'em, on several of their hits. So it was a natural transition, actually.

Watch Keith Allison Perform Louise

Allison remained with the band until 1975, by which time they were using the shortened title of the Raiders. He also worked with the Crickets, Roy Orbison, and Sonny & Cher, among others.

He released the solo album Keith Allison in Action, and served as Starrs musical director. He pursued a career in acting, then returned to music, joining the Waddy Watchel Band and appearing on Jerry Lee Lewis 2007 LP Last Man Standing.

I've had a great time, Allison said, reflecting on his career. I've enjoyed the highs and lows. It's like a roller coaster. But it's always been that way, up and down and up and down and up and down.

Remembering themusicians, actors, producers and others who havedied in 2021.

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The Lawless Masculinity of the GOP – The Atlantic

Posted: at 9:38 pm

Updated at 4:45 p.m. on November 20, 2021.

In 2008, Prime Minister Silvio Berlusconi invited his good friend Vladimir Putin to Sardinia, where Berlusconi had a vacation home, to discuss Italy and Russias business and energy ties. At a joint press conference held during the visit, the Russian journalist Natalia Melikova asked Putin a question about his rumored relationship with the former Olympic gymnast Alina Kabaeva. As an angry Putin stayed silent and cameras rolled, Berlusconi mimicked shooting Melikova. The Italian press dismissed this and similar acts by the prime minister as gaffes, treating them as little more than social faux pas. Yet they were much more than that. Humiliating women, or even mimicking shooting them, was central to Berlusconis strongman brand and a key to his power

Exercising an autocratic style of governance within a nominal democracy, Berlusconi cultivated an image as a virile leader untouchable by the law and able to have whatever and whomever he wanted, on demand. The commercial-television networks and ad agencies he owned mirrored his misogynist actions, saturating Italy with images of women in submissive and degrading roles. By 2011, when the Eurozone crisis forced Berlusconi out of office, he had survived 20 indictments and seven convictions for corruption, and a sex scandal involving a minor, without losing the support of his base or going to prison. But a United Nations Commission report that year warned that persistent portrayals of women as sex objects by politicians and the media lowered womens social status, leaving them vulnerable to discrimination. This man offends women and offends democracy, a feminist manifesto published in La Repubblica had warned two years earlier.

Authoritarianism has evolved over the past century, and old-school dictatorships are now joined by electoral autocracies. Yet at least one constant remains: Illiberal political solutions tend to take hold when increased gender equity and emancipation spark anxieties about male authority and status. A conquest-without-consequences masculinity, posing as a return to traditional values, tracks with authoritarianisms rise and parallels the discarding of the rule of law and accountability in politics. We commonly associate autocracy with state restrictions on behavior, but the removal of checks on actions deemed unethical in democratic contexts (lying, thievery, even rape and murder) is equally important to its operation and appeal.

Thats why its unsurprising to see a culture of lawless masculinity developing within the GOP, which adopted an authoritarian political culture during the Trump years. Renouncing democratic norms, the Republicans have normalized disinformation, election subversion, and violence as a means of governance, as expressed in their support for the January 6 coup attempt and the fiction that Donald Trump, not Joe Biden, won the 2020 election.

Read: The pussy presidency

Its symptomatic that a recent Fox News chyron trumpeted the need to embrace masculinity, and that Republican Senator Josh Hawley of Missouri now styles himself the defender of traditional masculine virtuesthings like courage and independence and assertiveness against a left trying to feminize men. The fist pump Hawley gave to the insurgents who had gathered to assault the Capitol hints at the real political agenda behind such calls for renewed male strength.

The anime-style video that Representative Paul Gosar of Arizona recently released, which spins a male fantasy of being acclaimed for murdering a female adversary, typifies the feelings of empowerment that come from belonging to a group that has legitimized criminal behavior. In it, an idealized Gosar saves the nation, attacking President Biden with swords and killing Representative Alexandria Ocasio-Cortez. While Democrats have called for Gosars expulsion from Congress and passed a measure on Wednesday to formally censure him, the strategic silence of the GOP leader Kevin McCarthy gives tacit approval to this public expression by a sitting lawmaker of murderous misogynist rage.

Flamboyant virility has always tended to go hand in hand with authoritarian politics, which is driven by the need to possess and exploit bodies, minds, national resources, and more. Its easy to laugh at the pectoral-baring performances of Mussolini and Vladimir Putin, and dismiss the rape jokes made by Jair Bolsonaro and Rodrigo Duterte of the Philippines, but the strongman style of leadership responds to perceived threats to male authority by upholding patriarchal privilege and the rights of men to satisfy their natural male desires.

Trump announced his allegiance to this tradition early on. I could stand in the middle of Fifth Avenue and shoot someone and I wouldnt lose voters, he asserted in January 2016. In October of that year, his assaultive approach to women became public through the leak of the 2005 Access Hollywood tape (When youre a star, they let you do it. You can do anything, Trump said). In spite of widespread predictions that the leak would be the end of the Trump campaign, it merely enhanced his macho profile.

The ethos of lawless masculinity is a lubricant of corruption, normalizing behaviors and redefining illegal or immoral acts as acceptable, from election fraud to sexual assault. These new norms attract collaborators who find it thrilling to be able to commit criminal acts with impunity. (Gosar used promises of blanket pardons to recruit participants for the January 6 coup attempt.)

From the June 2015 issue: Why it pays to be a jerk

Charismatic authoritarians diffuse models of power based on brute force, and soon the political system spawns individuals who earn status by imitating them. The Italian dictator Benito Mussolini had surrogates and proxies who repeated his hypermasculine performances and bombastic oratory, starting with his son-in-law, Galeazzo Ciano, who mimicked Il Duce's chin thrusts, earning the nickname The Jaw. The Italian writer Italo Calvino, who grew up during the dictatorship, recalled how his generation internalized the gestures, opinions, and behaviors of Mussolini from an early age.

Trumps success at birthing mini-Trumps is notable, considering that he governed in an open society for only four years (so far, at least). Mike Pompeo, who as secretary of state violated ethics standards and screamed obscenities at a female journalist, boasted about leading through swagger, while Florida Governor Ron DeSantiss 2018 campaign identity as a pitbull Trump defender has become so entrenched three years later that he routinely mimics the former presidents hand gestures.

In classic authoritarian fashion, Trump attracted collaborators by making it easier for men to act on their desires without fear of punishment. In 2019, his administration partly decriminalized domestic violence, limiting its definition to physical acts of harm (which effectively legalized sexual, emotional, economic, and psychological actions or threats of actions). Trump also defended men accused of sexual harassment and sexual assault, including Supreme Court Justice Brett Kavanaugh, and populated high-profile government positions with men, including Steve Bannon, who were accused of sexual harassment, domestic abuse, or inappropriate workplace behavior. How fitting that his chief of protocol, Sean Lawler, carried a horsewhip around in the office to intimidate co-workers.

Whether or not Trump returns to office, the GOP has made his brand of outlaw glamour its own. A real man takes what he wants, when he wants it, whether in the bedroom, the workplace, or politics, and pays no penalty. As the Republican quest to destroy democracy intensifies, so will abusive, predatory, and criminal behavior be further enabled and justified. For a century, getting away with it has been central to authoritarianisms allure, and it will be no different as the American version of illiberal rule unfolds.

This article originally stated that Silvio Berlusconi once grabbed a female traffic cop from behind and simulated copulation. Though accounts vary as to the origin and veracity of this anecdote, the video clip linked to in the description was from a fictional, satirical film about Berlusconi.

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Five areas Rutgers mens basketball must improve on – On The Banks

Posted: at 9:38 pm

Rutgers mens basketball suffered a bad loss on Thursday night in Chicago to DePaul 73-70. It was a continuation of what has been a frustrating and concerning start to the season. Lets review five areas that this team needs to address quickly as the schedule ramps up significantly in the next couple of weeks.

Rutgers has trailed at the half in all four games so far this season. Its a disturbing trend that needs to change quickly. Getting into the game cant include a feeling out period that leads to reckless and sloppy play. Better focus overall, establishing the post on offense while making rebounding a priority are ways to find a rhythm in the game. Rutgers isnt doing that. Poor decision making and forcing things on both ends continually puts this team in a hole. Geo Baker and Ron Harper Jr. need to assert control from the get go while as a team, they need to adjust to the speed of the game and have better recognition from the opening tip on.

A major issue is that Rutgers is lacking discipline on the defensive end. They have been a step slow in defending penetration and are taking too many chances trying to force turnovers. They have the length to cause opponents problems, but they arent using it to their advantage. Being more fundamentally sound with their defensive stance and footwork will allow them to keep in front of who they are defending. They arent forcing opponents to beat them off the dribble or require as much ball movement because they are late to spots and getting beaten off the ball. Last night, DePaul won the game from the three-point line down the stretch and Rutgers was late closing out on shooters.

These are unforced errors that need to be corrected.

It led to major foul trouble in the loss to DePaul. Head coach Steve Pikiell said after the game, If we could have defended without fouling, that would have helped us. That gave them a huge advantage. When we got down and guarded them, we did a good job.

Cliff Omoruyi is an example of a player taking too many risks on the defensive end. His second foul to send him to the bench in the first half was an overaggressive play. He was trying to block a shot without being in proper position. Blocking opponents from behind while they have position to the rim will draw a foul 100% of the time. While the third foul called on him for a push was a bad call since he didnt actually touch the player, he let it impact his decision making and picked up a fourth foul soon after with over 14 minutes to play in the game. He was effective last night, but not on the court nearly enough because of his foul trouble. An advanced stat is fouls committed per 40 minutes and Omoruyi charted at 8.4 last night. He wants more offensive opportunities but he needs to learn that thats not going to happen if he improve defensively.

Rebounding on the defensive end was an issue last season and was again on Thursday night. It goes back to footwork and being fundamentally sound by getting bodies on the opponent for effective box outs. DePaul is a very good rebounding team so far this season and they grabbed 14 offensive boards, which burned RU in a big way.

In regard to rebounding, Pikiell said after the game, You cant defend the free throw line. We fouled too much. When you are on the road, when you have that disparity, I was disappointed that we didnt rebound missed free throws. You have to make up for a lot of points when you put a team on the foul line that much. I was most disappointed with our free throw blockouts. I have to do a better job making sure we do that. We werent able to overcome that in the game, fouling was a huge issue. We have to do a better job of rebounding without fouling.

The offense isnt as much broken as its stuck in first gear. A lack of ball movement, making the extra pass and working the defense with ball reversals was mostly absent on Thursday night. There was way too many isolation plays and it led to poor shot selection and too many jump shots. There isnt enough movement off the ball and players are stagnant. This also negatively impacts rebounding as well.

When Rutgers takes mostly threes to start a game, its typically a bad sign. They missed their first three attempts in the first five possessions against DePaul and went 2 of 12 in the first half overall. They did a great job of making threes in the flow of the offense down the stretch once they were in rhythm in the game, making 8 of 15 from behind the arc in the second half.

As said in the section related to starting games faster, Rutgers has to do a better job of establishing the post early in games. Ron Harper Jr. and Cliff Omoruyi are matchup problems not only for low to mid major teams, they will be for a lot of Big Ten opponents as well. Taking the game to them and working inside out needs to be a priority.

Another issue is Rutgers is completely reliant on their halfcourt offense to score. They only had 3 points in transition against DePaul. They arent going to play with a fast tempo, but they need to be more opportunistic in running off of turnovers and defensive rebounds. While its obvious the quickness of Jacob Young leading the break is sorely missed, Id argue Myles Johnsons ability to throw accurate and timely outlet passes is missed even more. Rutgers isnt completing passes downfield off of defensive rebounds. Theyre dumping off to Geo Baker and Paul Mulcahy more times than not. Ron Harper Jr. and Aundre Hyatt have been the two best rebounders and both are capable of getting the ball up the court on their own.

Pikiells strategy in non-conference play is open to criticism but his intention is clear. He wants the opportunity to play a deeper rotation, mix and match lineups, keep his starters fresh ahead of the Big Ten grind and get development time for his younger players. The problem is due to issues mentioned just above, Rutgers hasnt had many opportunities for experimentation and development, while also playing his starters a ton of minutes.

You saw even more against DePaul, the shift back to Geo Baker as the primary ball handler is taking place. That being said, Paul Mulcahy played his best game of the season. He played with more confidence, hit some shots and provided some much needed energy on the floor. Pikiell said of his play, Paul does a lot of good things for us. He did a good job keeping the ball live, he gave us tremendous effort. We needed that and his maturity on the floor. While he did take a good amount of possessions as the lead ball handler, he looked more comfortable switching with Geo. Something to keep an eye on and Id be surprised if this wasnt the way forward long term.

While Aundre Hyatt is essentially playing like a sixth starter in terms of minutes played and being on the court late in games, the other bench players provided good support offensively in the first half against DePaul. Mawot Mag had 2 points, 3 assists and 2 rebounds along with playing with purpose on the offensive end. Jaden Jones hit a corner three in the flow of the offense that gave Rutgers a six point lead. He is a natural scorer who can score in all three phases. The problem is each are having issues on the defensive end. Because of that, Jones only got 2 minutes in the second half and Mag didnt get on the court at all.

Pikiell is a tough, old school coach in the sense that defense either keeps you on or takes you off the court. In these tight games, he is sticking with his veterans on the floor who have the best defensive understanding on the team. Hyatts transition into the rotation has been smooth in part because he has picked up the defensive principles quickly. For younger and inexperienced players like Jones and Mag, they are essentially learning on the fly. The issue is they are going to have to fill roles this season off the bench in Big Ten play. Taking lumps with them now seems beneficial long term in getting them ready for whats ahead. It will be interesting to compare minutes in this game to when they play at UMass next weekend as to whether they are given more time.

Caleb McConnell is a key player for this team, but his offensive play has been detrimental in the early going. He went 0 of 6 last night, but it was more the way he took shots and dribbled out possessions without moving the ball that hurt the most. He is the best defender on the team, brings toughness as well as an above average defender and rebounder. Pikiell is a coach who tries to inject confidence into his players, but figuring out a way to build that on the offensive end for McConnell while also improving the flow when he is on the court is vital moving forward.

With Cliff Omoruyi in foul trouble against DePaul, Ralph Gonzales-Agee and Dean Reiber were unable to provide enough production in his absence. Defensively, both struggled and Gonzales-Agee missed opportunities near the rim by pump faking and dribbling too much when he had the ball. If these are issues against DePaul, something has to improve before Big Ten play.

One adjustment to watch for is Pikiell going smaller by playing Ron Harper Jr. at the 5 and Aundre Hyatt at the 4. You can still have Geo on the court with a combination of McConnell, Mag, Jones and Mulcahy filling the other spots. Pikiell has talked about positionless basketball in the past and thats the type of lineup that could be effective when Cliff is in foul trouble moving forward. Dont expect Pikiell to give up on Gonzales-Agee too quickly, but having a plan B is going to be needed on certain nights.

The bottom line is that this loss is likely to create urgency for Pikiell to make decisions on the rotation sooner than he probably wanted to. And that means players accepting roles and prioritizing areas that make them the most productive as possible. We heard all offseason about how each player is focused on doing their role the best as they can, but whether their actual role thats needed actually matches up with the role they wanted needs to managed as well. Thats Pikiells job to manage and how this process sorts out remains to be seen.

Rutgers has played tight all season. They are truly a hunted team against the competition theyve faced so far. Their opponents play up to them and Rutgers has shown the troubling trend of playing down to its competition. They need leadership on the court to get out of that pattern. While Baker and Harper Jr. have been playing well, they also need to focus on getting their teammates to breath. I dont mean this as a criticism and that they arent trying to get players to relax more, but their battle scars make them capable of doing that. When this team feels the pressure, they press in their decision making or get overaggressive. Its leading to mistakes. It sounds simple, but in one sense they need to trust their abilities more and focus on the fundamentals. Trying to do too much or forcing the action is producing subpar results.

While the loss to DePaul is extremely disappointing and a ugly stain on their resume, this team needs to focus on the simple things. This team is tracking very similarly to the 2019-2020 team that took until mid-December to figure things out.

That 20 win team struggled in its first three games and lost its fourth contest of the season away from home to St. Bonaventure, who were rated No. 123 in KenPom. This Rutgers team struggled in the first three games of the season and lost its fourth contest away from home to DePaul, who were rated No. 123 coming into the matchup. Rutgers was No. 79 in KenPom after that loss two years ago, only to finish a program best No. 28 in March. This team is now at No. 75 in KenPom and with the strength of schedule in the Big Ten, there will be plenty of opportunities to make up for the loss to DePaul. The key is not allowing it to snowball and create a bigger hole.

The lack of creation on offense and lack of discipline on defense has raised serious concerns. The losses of Jacob Young and Myles Johnson have been felt. However, assuming this team wont evolve and be successful is not something I feel is warranted. If Rutgers can defend and rebound at a high level, which they are capable of doing, I truly believe more wins will follow than not. Offense obviously needs to improve and they have to play smarter. With this group and the way Pikiell coaches, everything comes from the defense first. Its a style and approach that isnt fun or popular, but its a proven formula thats worked.

Its not even Thanksgiving and this team is already at a gut check moment. They need to reevaluate themselves and each other in order to make corrections moving forward. The core group of players on this team have been through the wars and have responded well with their backs against the wall in the past. They arent in a desperate situation now, but in order to avoid that type of circumstance later this season, using this loss as a positive and learning from it is a must.

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Guest opinion: Floridians want our Everglades, oceans and coasts to be oil free – The News-Press

Posted: at 9:38 pm

Jon Paul J.P. Brooker| Special to The News-Press

Oil and water dont mix.

That adage applies to protecting Floridas precious ecosystems from oil drilling. Gov. Ron DeSantis and the Florida Legislature should permanently ban drilling for oil in or near any of the states aquatic ecosystems, including near our beaches, offshore on our reefs, or in our Everglades.

We have just seen another application to drill for oil near the Big Cypress Preserve. The Florida Department of Environmental Protection correctly acknowledged that would threaten highly sensitive aquatic ecosystems and upstream wildlife, and on Nov. 5 it denied Trend Explorations permit application. But companies have tried to explore for oil in the greater Everglades ecosystems for decades and this recent application wont be the last.

'This should be an outrage to the whole nation': Oil drilling permits would destroy historic Everglades, environmental groups tell feds

Guest opinion: New water control model brings 'significant improvement'

More like this: Legislation proposed enabling your right to know if Florida waters are safe

In a state where water quality has worsened and remains a top issue for voters, the last thing we need is the threat of oil spills in The Everglades or off our coasts. Red tide, Piney Point, blue green algal blooms, fish kills, a thousand dead manatees, thousands of acres of seagrass lost these severe water quality issues are reaching an apex in a state bordered on three sides by saltwater and filled with springs, lakes, streams and swamps.

Weve seen constant attempts to prospect for oil in the Gulf of Mexico and the South Atlantic. Those attempts are regularly shut down, because most Floridians dont want oil drilling off our coasts, spoiling our majestic views, threatening our world-class fisheries, and damaging our iconic coastal ecosystems and beaches that contribute billions in economic impact to the state. Floridians want our Everglades, oceans and coasts to be oil free.

A drop of water starting in the Kissimmee River can make its way into Lake Okeechobee, through The Everglades and its related ecosystems, and out to Florida Bay, the Florida Coral Reef Tract, and the open ocean. These ecosystems are interconnected, and their fates are intertwined. A failure of an oil drilling site in the Western Everglades isnt just a heartbreaking tragedy for panthers and other upland animals. Its a potential calamity for the seagrasses and redfish and tarpon that need clean freshwater sources to thrive in Florida Bay. That same drop of water making its way through South Florida watersheds can wreak havoc on our reefs if its tainted by oil as it travels through the glades.

Gov. DeSantis has emphasized protecting and restoring our states legendary waters. He has championed Everglades restoration efforts, steered millions to the Indian River Lagoon restoration, and embraced the Clean Waterways Act. Affirming a ban on oil drilling in The Everglades and off our coasts would affirm his commitment to providing Floridians with clean, abundant water for generations.

Jon Paul J.P. Brooker is the director of Florida Conservation and lawyer for Ocean Conservancy, the nations oldest marine conservation non-profit organization. He is a sixth generation Floridian.

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A Northeast Mississippi gym offers cryo therapy to members with injuries – WCBI

Posted: at 9:32 pm

Premiere Fitness opened 'Chill Out Cryo Therapy" a little more than one year ago.

TUPELO, Miss. (WCBI)- A Northeast Mississippi gym is helping folks recover from injuries, while also introducing people to the many uses for cryo therapy.

Justin Pace has just finished a workout at Premiere Fitness and now hes stepping into the Cryo Chamber.

The 29 year old competes in bodybuilding contests and uses the cryo chamber at least two times a week.

It releases some muscle tension, helps with body water, makes you feel like a whole different person, said Pace.

Premiere Fitness opened Chill Out Cryo Therapy a little more than one year ago.

Kaitlyn Kincade is the manager and cryo technician at Chill Out.

Cryo therapy is the use of cold temperatures to reduce inflammation in the body, its very beneficial for reducing muscle soreness, joint pain, nerve pain, arthritis, any type of inflammation in the body that causes any type of stiffness, said Kincade.

The sessions are short. Clients spend three minutes in the whole body chamber, while the temperature reaches minus 160.

The whole body chamber isnt the only option.

This is our isolated cryo machine, for people who dont want to do the whole body chamber, they have a specific area they want worked on, I can use wand and hand held cryo treatments, cryo skin 3.0 , newest addition, uses heat and cold to break down fat cells in the body, its spot treatment. And this is our red light therapy machine, I see a lot of people coming in for issues like eczema and rosacea, said Kincade.

Like the whole body chamber, liquid nitrogen is used, but it is targeted to the face and neck for cryo facials.

Kincade says cryo treatments have grown in popularity for all ages.

We opened it up thinking it would be a benefit to our gym members but weve had a lot of the public support and community has really liked it so far, said Kincade.

CRYO facials are also available and are used to treat acne and other skin issues.

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CWU Philosophy Department comes together to discuss Life after Death. – The Observer

Posted: at 9:21 pm

The possibility of immortality, death in marginalized communities, and the advent of pharmaceuticals in delaying death make for intriguing topics to discuss and thanks to the Philosophy Department. These topics and more were covered by varying experts.

On Nov. 15, members of the Philosophy department convened a panel on Zoom to discuss varying statistics, viewpoints and stances regarding the subject of death. Some instances included the debate between Daoist and Western philosophy, the deaths of peoples of different races and ethnicities, how people, such as physicians, choose to end their lives and many other interesting topics.

The primary panelists included Cynthia Coe, David Schwan, Griff Tester and Jeff Dippmann. Dippmanns completion of a recent research project on Daoism and mortality was the catalyst for this panel. Schwan was the lead panelist and moderator of this discussion.

The topics included the saturation of death in the LGBTQ community, where Tester explained how those in the LGBTQ community were so used to death and abandonment from family, friends and other support systems. For that community, death became commonplace.

Here were a group of people, or more groups of people, who upon getting sick with HIV/AIDS, were ostracized by the communities they were a part of, Tester said. They had no one to take care of them, so they had to care for themselves and each other.

Dippmann, professor and department chair of Philosophy and Religious Studies, provided an introspective on Daoist philosophy and the concept of immortality, in addition to the lessons one may learn as an immortal. Dippmann cited a work of Bernard Williams (1929-2003) about the tedium of mortality and how in the work, a fictionalized opera, an elixir-taking woman lived for 300 years and found life as, boring, indifferent, and cold. She stops taking her elixir and dies an immediate death.

Coe, also a professor of Philosophy and Religious Studies, provided insight into pharmaceutical influences on death and how people may elect to end their lives. She provided the perspective of how pharmaceuticals, while they may abate death, did not guarantee quality of life.

There are many amazing things that have happened as the result of medical intervention in human life. Human lifespans have increased dramatically over the planet of the last 200 years, Coe said, before proceeding to cite Dr. Atul Gawande, a surgeon. But particularly at the end of life, medicine can cause more harm than good. Scientific advances have turned the processes of aging and dying into medical experiences, matters to be managed by health care professionals and we in the medical world have proved alarmingly unprepared for it.

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Growth Opportunities in Synthetic Biology, AI Augmented Diagnostics, Microbiome Enablers, Biomarker Discovery and Lab Automation 2021 -…

Posted: at 9:15 pm

DUBLIN, November 19, 2021--(BUSINESS WIRE)--The "Growth Opportunities in Synthetic Biology, AI Augmented Diagnostics, Microbiome Enablers, Biomarker Discovery, and Lab Automation" report has been added to ResearchAndMarkets.com's offering.

This edition of the Life Science, Health & Wellness Technology Opportunity Engine (TOE) focuses on microbiome-based technologies, such as high throughput isolation and culturing of microbes, microbial biomarker-based diagnostics, microbial single cell genomic analysis, and so on.

Recent advances in synthetic biology platforms along with developments in lab automation and microfluidics technologies, which are bolstering the field have also been covered. Innovations around artificial intelligence (AI) and machine learning (ML) augmented diagnostics have been highlighted, and this includes both image-based diagnostics and molecular diagnostics. Many of the innovations covered in this issue support new biomarker discovery and novel therapeutics development.

The Life Science, Health & Wellness TOE will feature disruptive technology advances in the global life sciences industry. The technologies and innovations profiled will encompass developments across genetic engineering, drug discovery and development, biomarkers, tissue engineering, synthetic biology, microbiome, disease management, as well as health and wellness among several other platforms.

The Health & Wellness cluster tracks developments in a myriad of areas including genetic engineering, regenerative medicine, drug discovery and development, nanomedicine, nutrition, cosmetic procedures, pain and disease management and therapies, drug delivery, personalized medicine, and smart healthcare.

Key Topics Covered:

Innovations in Life Sciences, Health & Wellness

High-Throughput Microbial, Cultivation, Isolation and Screening Platform

Automation in Microbial Culture

Galt Inc. - Investor Dashboard

Noninvasive Colorectal Cancer Screening Testing

Detection of Colon Polyps Thorough Microbial Biomarkers

Metabiomics Corp. - Investor Dashboard

Microbiome Single-Cell Genomic Analysis

Therapeutics and Diagnostic Development Tool

Bitbiome Inc. - Investor Dashboard

Picodroplet Microfluidic Technology for Single-Cell Analysis

Acceleration of Antibody Discovery and Cell-Line Development Processes Through Picodroplet Technology

Sphere Fluidics - Investor Dashboard

Clostridium-Assisted Drug Development Platform Supports Oral Drug Delivery

The Engineered Strain of Clostridium Serves as a Live Biotherapeutic Product

Chain Biotechnology - Investor Dashboard

Xenonucleic Acid and Superbdna Technologies for Diagnostics

XNA and Superbdna Offer High Sensitivity and Specificity in Detection of Cancer and COVID-19

Diacarta - Investor Dashboard

Robotic Cloud Lab for Drug Discovery and Development

Robotic Cloud Labs Revolutionize the Scientists' Workday

Strateos - Investor Dashboard

Developing Personalized Medicine to Slow Cell Senescence

Cancer Biomarker Detection for Faster Diagnosis

Developing Targeted Protein Degradation Technology

Automated Library Preparation for Next-Generation Sequencing

Machine Learning and AI-Based Cardiovascular Imaging Solutions

AI and Big Data-Enabled Genomic Diagnostics Targeting Rare Diseases

Exosomes Characterization to Study Disease-Specific Biomarkers

Machine Learning-Enabled Mutation Calling to Detect Cancer

Companies Mentioned

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Bitbiome Inc.

Chain Biotechnology

Diacarta

Galt Inc.

Metabiomics Corp.

Sphere Fluidics

Strateos

For more information about this report visit https://www.researchandmarkets.com/r/btqnmd

About ResearchAndMarkets.com

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View source version on businesswire.com: https://www.businesswire.com/news/home/20211119005345/en/

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Growth Opportunities in Synthetic Biology, AI Augmented Diagnostics, Microbiome Enablers, Biomarker Discovery and Lab Automation 2021 -...

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