Pilot testing of a novel surgical simulator for endoscopic zenker’s diverticulotomy

Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/136304/1/lary26129.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/136304/2/lary26129_am.pd

Differential expression and prognostic value of long nonâ coding RNA in HPVâ negative head and neck squamous cell carcinoma

BackgroundLong nonâ coding RNA (lncRNA) has emerged as a new avenue of interest due to its various biological functions in cancer. Abnormal expression of lncRNA has been reported in other malignancies but has been understudied in head and neck squamous cell carcinoma (HNSCC).MethodsThe lncRNA expression was interrogated via quantitative realâ time polymerase chain reaction (qRTâ PCR) array for 19 human papillomavirus (HPV)â negative HNSCC tumorâ normal pairs. The Cancer Genome Atlas (TCGA) was used to validate these results. The association between differentially expressed lncRNA and survival outcomes was analyzed.ResultsDifferential expression was validated for 5 lncRNA (SPRY4â IT1, HEIH, LUCAT1, LINC00152, and HAND2â AS1). There was also an inverse association between MEG3 expression (not significantly differentially expressed in TCGA tumors but highly variable expression) and 3â year recurrenceâ free survival (RFS).ConclusionWe identified and validated differential expression of 5 lncRNA in HPVâ negative HNSCC. Low MEG3 expression was associated with favorable 3â year RFS, although the significance of this finding remains unclear.Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/144638/1/hed25136_am.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/144638/2/hed25136.pd

Impact of HIV Infection and Kaposi Sarcoma on Human Herpesvirus-8 Mucosal Replication and Dissemination in Uganda

Kaposi sarcoma (KS) is the leading cause of cancer in Uganda and occurs in people with and without HIV. Human herpesvirus-8 (HHV-8) replication is important both in transmission of HHV-8 and progression to KS. We characterized the sites and frequency of HHV-8 detection in Ugandans with and without HIV and KS.Participants were enrolled into one of four groups on the basis of HIV and KS status (HIV negative/KS negative, HIV positive/KS negative, HIV negative/KS positive, and HIV positive/KS positive). Participants collected oral swabs daily and clinicians collected oral swabs, anogenital swabs, and plasma samples weekly over 4 weeks. HHV-8 DNA at each site was quantified by polymerase chain reaction (PCR).78 participants collected a total of 2063 orals swabs and 358 plasma samples. Of these, 428 (21%) oral swabs and 96 (27%) plasma samples had detectable HHV-8 DNA. HHV-8 was detected more frequently in both the oropharynx of persons with KS (24 (57%) of 42 persons with KS vs. 8 (22%) of 36 persons without, p = 0.002) and the peripheral blood (30 (71%) of 42 persons with KS vs. 8 (22%) of 36 persons without, p<0.001). In a multivariate model, HHV-8 viremia was more frequent among men (IRR = 3.3, 95% CI = 1.7-6.2, p<0.001), persons with KS (IRR = 3.9, 95% CI = 1.7-9.0, p = 0.001) and persons with HIV infection (IRR = 1.7, 95% CI = 1.0-2.7, p = 0.03). Importantly, oral HHV-8 detection predicted the subsequent HHV-8 viremia. HHV-8 viremia was significantly more common when HHV-8 DNA was detected from the oropharynx during the week prior than when oral HHV-8 was not detected (RR = 3.3, 95% CI = 1.8-5.9 p<0.001). Genital HHV-8 detection was rare (9 (3%) of 272 swabs).HHV-8 detection is frequent in the oropharynx and peripheral blood of Ugandans with endemic and epidemic KS. Replication at these sites is highly correlated, and viremia is increased in men and those with HIV. The high incidence of HHV-8 replication at multiple anatomic sites may be an important factor leading to and sustaining the high prevalence of KS in Uganda

Paired phase II trials evaluating cetuximab and radiotherapy for low risk HPV associated oropharyngeal cancer and locoregionally advanced squamous cell carcinoma of the head and neck in patients not eligible for cisplatin

BackgroundAlternative therapeutic strategies are needed for localized oropharyngeal carcinoma. Cetuximab represents a potential option for those ineligible for cisplatin or, until recently, an agent for de‐escalation in low risk HPV+ oropharyngeal carcinoma (OPSCC). Our objective was to define the toxicity and efficacy of cetuximab‐radiotherapy.MethodsWe conducted paired phase II trials evaluating cetuximab‐radiotherapy in two cohorts (a) low risk HPV+ OPSCC and (b) cisplatin ineligible. The mean follow‐up was 48 months.ResultsForty‐two patients were enrolled in cohort A with a 2‐year disease free survival (DFS) of 81%. Twenty‐one patients were enrolled in cohort B prior to closure due to adverse outcomes with a 2‐year DFS of 37%. Severe toxicities were seen in 60% of patients, 30% required enteral nutrition.ConclusionAmong cisplatin ineligible patients, cetuximab treatment engendered poor outcomes. Rates of severe toxicities were on par with platinum‐based regimens suggesting that cetuximab is not a benign treatment.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/156234/2/hed26085.pdfhttp://deepblue.lib.umich.edu/bitstream/2027.42/156234/1/hed26085_am.pd

What is missing in autonomous discovery: Open challenges for the community

Self-driving labs (SDLs) leverage combinations of artificial intelligence, automation, and advanced computing to accelerate scientific discovery. The promise of this field has given rise to a rich community of passionate scientists, engineers, and social scientists, as evidenced by the development of the Acceleration Consortium and recent Accelerate Conference. Despite its strengths, this rapidly developing field presents numerous opportunities for growth, challenges to overcome, and potential risks of which to remain aware. This community perspective builds on a discourse instantiated during the first Accelerate Conference, and looks to the future of self-driving labs with a tempered optimism. Incorporating input from academia, government, and industry, we briefly describe the current status of self-driving labs, then turn our attention to barriers, opportunities, and a vision for what is possible. Our field is delivering solutions in technology and infrastructure, artificial intelligence and knowledge generation, and education and workforce development. In the spirit of community, we intend for this work to foster discussion and drive best practices as our field grows

Mutational profiles of persistent/recurrent laryngeal squamous cell carcinoma

BackgroundWe sought to describe targeted DNA sequencing data of persistent/recurrent laryngeal squamous cell carcinoma (LSCC) and to compare gene‐specific alteration frequencies with that of primary, untreated LSCC specimens from The Cancer Genome Atlas (TCGA).MethodsThe tumors of 21 patients with persistent/recurrent LSCC were subjected to targeted DNA sequencing using the Ion AmpliSeq Comprehensive Cancer Panel. Gene‐specific alteration frequencies were compared (Chi‐Square test) to primary, untreated LSCC sequencing data from TCGA using the cBioPortal platform.ResultsPersistent/recurrent LSCC was characterized by a high rate of inactivating alterations in TP53 (38.1%) and CDKN2A (33%), amplification events of CCND1 (19.1%), and ERBB2 (14.3%), and NOTCH1 (19.1%) mutations. Comparison of primary vs persistent/recurrent LSCC revealed significant differences in alteration frequencies of eight critical genes: BAP1, CDKN2A, DCUN1D1, MSH2, MTOR, PIK3CA, TET2, and TP53.ConclusionsOur results provide preliminary support for a distinct mutational profile of persistent/recurrent LSCC that requires validation in larger cohorts.Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/147873/1/hed25444.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/147873/2/hed25444_am.pd

Impact of American Joint Committee on Cancer Eighth Edition clinical stage and smoking history on oncologic outcomes in human papillomavirus‐associated oropharyngeal squamous cell carcinoma

BackgroundThe purpose of this study was to evaluate the AJCC eighth edition clinical staging system for human papillomavirus (HPV)‐associated oropharyngeal squamous cell carcinoma and to further understand how clinical stage and smoking history affect oncologic outcomes. The purpose of this study was to present the understanding of how clinical stage and smoking history affect oncologic outcomes in human papillomavirus (HPV)‐associated oropharyngeal squamous cell carcinoma (SCC) is critical for selecting patients for treatment deintensification.MethodsKaplan‐Meier and Cox regression were used to evaluate overall survival (OS), locoregional recurrence‐free survival (LRFS), and distant recurrence‐free survival (DRFS). Concordance statistics (C‐indices) were used to compare discriminating ability.ResultsThe OS and DRFS but not LRFS were significantly distributed using the American Joint Committee on Cancer (AJCC) seventh and eighth editions criteria. The C‐indices for OS, LRFS, and DRFS were 0.57, 0.54, and 0.60, respectively, using the AJCC seventh edition, and 0.63, 0.53, and 0.65, respectively, using the AJCC eighth edition. On multivariate analysis, 1 + pack‐year smoking history correlated with OS (hazard ratio [HR] 1.96; 95% confidence interval [CI] 1.2‐3.1; P < .01) but not LRFS or DRFS.ConclusionThese results support implementation of the AJCC eighth edition for HPV‐associated oropharyngeal SCC. Clinical stage may be more important than smoking history in selection for deintensification.Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/148352/1/hed25336_am.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/148352/2/hed25336.pd

Fairness at Trial: The Impact of Procedural Justice and Other Experiential Factors on Criminal Defendants' Perceptions of Court Legitimacy in Poland

A large body of research supports the procedural justice hypothesis that quality of treatment matters more than outcomes for institutional legitimacy. How fairness matters across legal institutions and geographic settings remains an open question, however. This article uses a survey of criminal defendants to test the factors associated with perceived legitimacy of courts in Poland, a country whose judiciary is currently subject to intense political contestation. The findings confirm the primacy of procedural justice, while also illustrating the influence of instrumental performance factors such as time and court organization. This suggests that in contexts of political transition with disputed legal institutions, citizens’ contact with procedurally fair, operationally efficient institutions can support the legitimacy of authorities and strengthen the rule of law

New insights into the synergism of nucleoside analogs with radiotherapy

Nucleoside analogs have been frequently used in combination with radiotherapy in the clinical setting, as it has long been understood that inhibition of DNA repair pathways is an important means by which many nucleoside analogs synergize. Recent advances in our understanding of the structure and function of deoxycytidine kinase (dCK), a critical enzyme required for the anti-tumor activity for many nucleoside analogs, have clarified the mechanistic role this kinase plays in chemo- and radio-sensitization. A heretofore unrecognized role of dCK in the DNA damage response and cell cycle machinery has helped explain the synergistic effect of these agents with radiotherapy. Since most currently employed nucleoside analogs are primarily activated by dCK, these findings lend fresh impetus to efforts focused on profiling and modulating dCK expression and activity in tumors. In this review we will briefly review the pharmacology and biochemistry of the major nucleoside analogs in clinical use that are activated by dCK. This will be followed by discussions of recent advances in our understanding of dCK activation via post-translational modifications in response to radiation and current strategies aimed at enhancing this activity in cancer cells