tbuckley/cabot-search huggingface dataset:
Cabozantinib as First-line Treatment in Patients With Metastatic Collecting Duct Renal Cell Carcinoma
Authors: Giuseppe Procopio, Pierangela Sepe, Melanie Claps, Sebastiano Buti, Maurizio Colecchia, Patrizia Giannatempo, Valentina Guadalupi, Luigi Mariani, Luca Lalli, Giovanni Fucà, Filippo de Braud, Elena Verzoni
Journal: JAMA Oncology (2022)

Metastatic collecting duct carcinoma (mCDC) is a rare type of non-clear cell renal cell carcinoma (ncRCC) with poor prognosis and no standard treatments. Despite retrospective series that have documented the benefit of cabozantinib in ncRCC, no prospective trials have evaluated this treatment in mCDC.To determine whether cabozantinib is an active treatment in patients with mCDC.The caBozantinib in cOllectiNg ductS Renal Cell cArcInoma (BONSAI) trial was an open-label, single-arm, phase 2 clinical trial carried out between January 2018 and November 2020 at a single academic center with data cut off in September 2021 on behalf of the the Italian Network for Research in Urologic-Oncology (Meet-URO 2). Eligible patients had histologic diagnosis of centrally confirmed mCDC with measurable disease according to Response Evaluation Criteria in Solid Tumors (RECIST; version 1.1). In total, 25 patients were screened.Patients received cabozantinib, 60 mg orally once daily, until disease progression, unacceptable toxic effects, or withdrawal of consent.The primary end point was objective response rate (ORR) per RECIST, version 1.1.At data cut off, of 25 patients enrolled, 23 started treatment because 2 were excluded after failing the screening process at pathologic review. The median follow-up cannot be estimated using the reverse Kaplan-Meier estimator. The median time to censoring was 11 months (95% CI, 0-22 months). Median (range) age was 66 (53-74) years. As best overall response, 3 patients presented stable disease, 1 patient achieved a complete response, and 7 a partial response. The ORR was 35% (95% CI, 16%-57%). The median progression-free survival was 4 months (95% CI, 3-13 months). The median OS was 7 months (95% CI, 3-31 months). All patients reported at least 1 grade (G) 1 to 2 adverse event (AE). The most common G1 to G2 AEs were fatigue (14 [60%]), anorexia (9 [39%]), hand-foot syndrome (7 [30%]), hypothyroidism (7 [30%]), mucositis (7 [30%]), diarrhea (5 [22%]), and hypertension (3 [13%]). Six G3 AEs were reported: 2 arterial hyperthension, 1 pulmonary thromboembolism, 1 bleeding, and 2 fatigue. There were no permanent discontinuations from the study owing to AEs. Four patients (17%) required dose reduction to 40 mg, and 4 (17%) required a transitory interruption to manage toxic effects.The study met the ORR primary end point, showing encouraging efficacy of cabozantinib in untreated patients with mCDC. Further investigations to advance the molecular understanding of this tumor are ongoing.ClinicalTrials.gov Identifier: NCT03354884.
Erratum
Journal: Hepatology (2022)

In reference to Spirli et al., [1] we have become aware of an error in Figure 6A.This figure is intended to show that ER Calcium depletion (in this case using thapsigargin, an inhibitor of SERCA, the pump that allows ER Calcium entry) results in activation of the ERK pathway.The blot shows an example of Western blots from which the averages between phosphorylated ERK and total ERK shown in the bar graphs are then calculated.Forensic analysis concluded that Figure 6A contains lines seemingly duplicated for re-use in separate groups, as the bottom line 1-3 appears the same as lines 4-6.As such this figure should be considered erroneous (or falsified).However, reducing ER Calcium by another mean (chelation by TPEN) still increases ERK phosphorylation, and thus the results and interpretation of the paper remain valid.
Evaluation of Optimal Threshold of Neutrophil-Lymphocyte Ratio and Its Association With Survival Outcomes Among Patients With Head and Neck Cancer
Authors: Sung Jun Ma, Han Yu, Michael Khan, Jasmin Gill, Sharon Santhosh, Udit Chatterjee, Austin Iovoli, Mark Farrugia, Hemn Mohammadpour, Kimberly Wooten, Vishal Gupta, Ryan McSpadden, Moni A. Kuriakose, Michael R. Markiewicz, Wesley L. Hicks, Mary E. Platek, Mukund Seshadri, Andrew D. Ray, Elizabeth Repasky, Anurag K. Singh
Journal: JAMA Network Open (2022)

<h3>Importance</h3> Given the role of inflammation in cancer progression, neutrophil-lymphocyte ratio (NLR) from peripheral blood has been suggested as a readout of systemic inflammation and a prognostic marker in several solid malignant neoplasms. However, optimal threshold for NLR in US patients with head and neck cancer remains unclear. <h3>Objective</h3> To evaluate the optimal NLR threshold as a potential prognostic biomarker for survival outcomes. <h3>Design, Setting, and Participants</h3> This retrospective cohort study was conducted at a single institution. Participants included 496 patients with nonmetastatic head and neck cancer who underwent chemoradiation from April 2007 to March 2021. Statistical analysis was performed from September to December 2021. <h3>Exposures</h3> High vs low NLR. <h3>Main Outcomes and Measures</h3> Overall survival (OS) and cancer-specific survival (CSS). <h3>Results</h3> A total of 496 patients (411 male patients [82.9%]; 432 White patients [87.1%]; 64 patients with other race or ethnicity [12.9%]; median [IQR] age, 61 [55-67] years) were identified. Median (IQR) follow-up was 44.4 (22.8-74.0) months. Thresholds of NLR for both OS and CSS were 5.71. High NLR above 5.71 was associated with worse OS (adjusted hazard ratio [aHR], 1.97; 95% CI, 1.26-3.09;<i>P</i> = .003) and CSS (aHR, 2.33; 95% CI, 1.38-3.95;<i>P</i> = .002). On logistic multivariable analysis, patients were more likely to have high NLR if they had higher T and N staging (T3-4: aOR, 4.07; 95% CI, 1.92-9.16;<i>P</i> &lt; .001; N2: aOR, 2.97; 95% CI, 1.04-9.17;<i>P</i> = .049; N3: aOR, 11.21; 95% CI, 2.84-46.97;<i>P</i> &lt; .001), but less likely if they had a good performance status (Karnofsky Performance Status 90-100: aOR, 0.29; 95% CI, 0.14-0.59;<i>P</i> &lt; .001). Among 331 patients (66.7%) with available human papillomavirus (HPV) data, high NLR was not associated with OS (HPV-negative: aHR, 2.46; 95% CI, 0.96-6.31;<i>P</i> = .06; HPV-positive: aHR, 1.17; 95% CI, 0.38-3.56;<i>P</i> = .78) and CSS (HPV-negative: aHR, 2.55; 95% CI, 0.81-7.99;<i>P</i> = .11; HPV-positive: aHR, 1.45; 95% CI, 0.44-4.76;<i>P</i> = .54). <h3>Conclusions and Relevance</h3> High NLR was associated with worse survival. Patients with substantial disease burden and poor performance status were more likely to have high NLR. These findings suggest that further studies would be warranted to investigate the role of such prognostic marker to identify patients at risk to tailor interventions.
Prediction of survival with intensive chemotherapy in acute myeloid leukemia
Authors: Koji Sasaki, Farhad Ravandi, Tapan Kadia, Courtney DiNardo, Gautam Borthakur, Nicholas Short, Nitin Jain, Naval Daver, Elias Jabbour, Guillermo Garcia‐Manero, Joseph Khoury, Sergej Konoplev, Sanam Loghavi, Keyur Patel, Guillermo Montalban‐Bravo, Lucia Masarova, Marina Konopleva, Hagop Kantarjian
Journal: American Journal of Hematology (2022)

Progress with intensive chemotherapy and supportive care measures has improved survival in newly diagnosed acute myeloid leukemia (AML). Predicting outcome helps in treatment decision making. We analyzed survival as the treatment endpoint in 3728 patients with newly diagnosed AML treated with intensive chemotherapy from 1980 to 2021. We divided the total study group (3:1 basis) into a training (n = 2790) and a validation group (n = 938). The associations between survival and 27 characteristics were investigated. In the training cohort, the multivariate analysis identified 12 consistent adverse prognostic variables independently associated with worse survival: older age, therapy-related myeloid neoplasm, worse performance status, cardiac comorbidity, leukocytosis, anemia, thrombocytopenia, elevated creatinine and lactate dehydrogenase, cytogenetic abnormalities, and the presence of infection at diagnosis except fever of unknown origin. We categorized patients into four prognostic groups, favorable (7%), intermediate (43%), poor (39%), and very poor (11%) with estimated 5-year survival rates of 69%, 36%, 13%, and 3% respectively (p < .001). The predictive model was validated in an independent cohort. In a subset of patients with molecular mutation profiles, adding the mutation profiles after accounting for the effects of previous factors identified NPM1 (favorable), PTPN11, and TP53 (both unfavorable) mutations as molecular prognostic factors. The new proposed predictive model for survival with intensive chemotherapy in patients with AML is robust and can be used to advise patients regarding their prognosis, to modify therapy in remission (e.g., proposing allogeneic stem cell transplantation in first remission), and to compare outcome and benefits on future investigational therapies.
Short-term senolytic treatment: a paradigm to promote fracture repair during aging
Authors: Isabel Beerman, Nathan Basisty, Rafael de Cabo
Journal: Journal of Clinical Investigation (2022)

Increased age is blamed for a wide range of bone physiological changes, and although the underlying mechanisms affecting the decreased capacity for fracture healing are not fully understood, they are clearly linked to changes at the cellular level. Recent evidence suggests potential roles of senescent cells in response to most tissue injuries, including bone fractures. In this issue of the JCI, Liu, Zhang, and co-authors showed that a senolytic drug cocktail cleared senescent cells from the callus and improved bone fracture repair in aged mice. Understanding how senescent cells emerge at fracture sites and how their timely removal improves fracture healing should provide insights for effective therapeutic approaches in old age.
Measuring what counts to improve quality of care
Authors: Toby Garrood
Journal: BMJ (2022)

consultant rheumatologist and clinical directorIn the US in 1961, Robert McNamara joined the Kennedy administration as secretary of defence, bringing with him a strong track record in the application of metrics to complex problems.During the second world war he was part of the team that applied statistical approaches to improve the efficiency of bombing raids and subsequently used his expertise to help turn around the fortunes of the Ford Motor Company, whose president he became in 1960.He applied his previously successful uses of metrics to US military strategy during the Vietnam war.However, measures such as ratios of casualties, use of ordnance, and land occupation failed to take into account those factors that were harder to quantify, such as strategy, leadership, and morale.The failure of this approach was instrumental in McNamara's resignation in 1968.
Androgen conspires with the CD8 <sup>+</sup> T cell exhaustion program and contributes to sex bias in cancer
Authors: Hyunwoo Kwon, Johanna M. Schafer, No-Joon Song, Satoshi Kaneko, Anqi Li, Tong Xiao, Anjun Ma, Carter Allen, Komal Das, Lei Zhou, Brian Riesenberg, Yuzhou Chang, Payton Weltge, Maria Velegraki, David Y. Oh, Lawrence Fong, Qin Ma, Debasish Sundi, Dongjun Chung, Xue Li, Zihai Li
Journal: Science Immunology (2022)

Sex bias exists in the development and progression of nonreproductive organ cancers, but the underlying mechanisms are enigmatic. Studies so far have focused largely on sexual dimorphisms in cancer biology and socioeconomic factors. Here, we establish a role for CD8+ T cell-dependent antitumor immunity in mediating sex differences in tumor aggressiveness, which is driven by the gonadal androgen but not sex chromosomes. A male bias exists in the frequency of intratumoral antigen-experienced Tcf7/TCF1+ progenitor exhausted CD8+ T cells that are devoid of effector activity as a consequence of intrinsic androgen receptor (AR) function. Mechanistically, we identify a novel sex-specific regulon in progenitor exhausted CD8+ T cells and a pertinent contribution from AR as a direct transcriptional transactivator of Tcf7/TCF1. The T cell-intrinsic function of AR in promoting CD8+ T cell exhaustion in vivo was established using multiple approaches including loss-of-function studies with CD8-specific Ar knockout mice. Moreover, ablation of the androgen-AR axis rewires the tumor microenvironment to favor effector T cell differentiation and potentiates the efficacy of anti-PD-1 immune checkpoint blockade. Collectively, our findings highlight androgen-mediated promotion of CD8+ T cell dysfunction in cancer and imply broader opportunities for therapeutic development from understanding sex disparities in health and disease.
A unique mode of nucleic acid immunity performed by a multifunctional bacterial enzyme
Authors: S.M. Nayeemul Bari, Lucy Chou-Zheng, Olivia Howell, Motaher Hossain, Courtney M. Hill, Tori A. Boyle, Katie Cater, Vidya Sree Dandu, Alexander Thomas, Barbaros Aslan, Asma Hatoum-Aslan
Journal: Cell Host & Microbe (2022)

The perpetual arms race between bacteria and their viruses (phages) has given rise to diverse immune systems, including restriction-modification and CRISPR-Cas, which sense and degrade phage-derived nucleic acids. These complex systems rely upon production and maintenance of multiple components to achieve antiphage defense. However, the prevalence and effectiveness of minimal, single-component systems that cleave DNA remain unknown. Here, we describe a unique mode of nucleic acid immunity mediated by a single enzyme with nuclease and helicase activities, herein referred to as Nhi (nuclease-helicase immunity). This enzyme provides robust protection against diverse staphylococcal phages and prevents phage DNA accumulation in cells stripped of all other known defenses. Our observations support a model in which Nhi targets and degrades phage-specific replication intermediates. Importantly, Nhi homologs are distributed in diverse bacteria and exhibit functional conservation, highlighting the versatility of such compact weapons as major players in antiphage defense.
Estimated Incidence of Seasonal Influenza in China From 2010 to 2020 Using a Multiplier Model
Authors: Qiang Wang, Liuqing Yang, Chang Liu, Hui Jin, Leesa Lin
Journal: JAMA Network Open (2022)

This study did have limitations.Although we estimated all model inputs as accurately as possible, considerable uncertainty in these parameters and therefore in the overall results remains.Additionally, some parameters in February and March 2020 might have differed from previous seasons due to the COVID-19 epidemic and China's lockdown policy.This study provided a tool to estimate seasonal influenza burden and appealed to enhance influenza surveillance ability in China.The reported number of influenza cases was considerably less than the true number of cases.
Correction: Absence of Cytomegalovirus in Glioblastoma and Other High-grade Gliomas by Real-time PCR, Immunohistochemistry, and <i>In Situ</i> Hybridization
Authors: Matthias Holdhoff, Gunes Guner, Fausto J. Rodriguez, Jessica L. Hicks, Qizhi Zheng, Michael S. Forman, Xiaobu Ye, Stuart A. Grossman, Alan K. Meeker, Christopher M. Heaphy, Charles G. Eberhart, Angelo M. De Marzo, Ravit Arav-Boger
Journal: Clinical Cancer Research (2022)

In the original version of this article (1), the same image was used for Fig. 3A and B. The error has been corrected in the latest online HTML and PDF versions of the article. The authors regret the error.
Screening and vaccination against COVID-19 to minimise school closure: a modelling study
Authors: Elisabetta Colosi, Giulia Bassignana, Diego Andrés Contreras, Canelle Poirier, Pierre-Yves Boëlle, Simon Cauchemez, Yazdan Yazdanpanah, Bruno Lina, Arnaud Fontanet, Alain Barrat, Vittoria Colizza
Journal: The Lancet Infectious Diseases (2022)
Predictors of relapse, death or heart transplantation in myocarditis before the introduction of immunosuppression: negative prognostic impact of female gender, fulminant onset, lower ejection fraction and serum autoantibodies
Authors: Anna Baritussio, Alessandro Schiavo, Cristina Basso, Andrea Silvio Giordani, Chun‐yan Cheng, Elena Pontara, Maria Grazia Cattini, Elisa Bison, Nicoletta Gallo, Monica De Gaspari, Elisa Carturan, Gaetano Thiene, Giuseppe Tarantini, Mario Plebani, Stefania Rizzo, Dario Gregori, Sabino Iliceto, Renzo Marcolongo, Alida Linda Patrizia Caforio
Journal: European Journal of Heart Failure (2022)
KLF6 facilitates differentiation of odontoblasts through modulating the expression of P21 in vitro
Authors: Zhuo Chen, Wenzhi Wu, Chen Zheng, Yanhua Lan, Huizhi Xie, Zhijian Xie
Journal: International Journal of Oral Science (2022)

Multiple signaling pathways are involved in the regulation of cell proliferation and differentiation in odontogenesis and dental tissue renewal, but the details of these mechanisms remain unknown. Here, we investigated the expression patterns of a transcription factor, Krüppel-like factor 6 (KLF6), during the development of murine tooth germ and its function in odontoblastic differentiation. KLF6 was almost ubiquitously expressed in odontoblasts at various stages, and it was co-expressed with P21 (to varying degrees) in mouse dental germ. To determine the function of Klf6, overexpression and knockdown experiments were performed in a mouse dental papilla cell line (iMDP-3). Klf6 functioned as a promoter of odontoblastic differentiation and inhibited the proliferation and cell cycle progression of iMDP-3 through p21 upregulation. Dual-luciferase reporter assay and chromatin immunoprecipitation showed that Klf6 directly activates p21 transcription. Additionally, the in vivo study showed that KLF6 and P21 were also co-expressed in odontoblasts around the reparative dentin. In conclusion, Klf6 regulates the transcriptional activity of p21, thus promoting the cell proliferation to odontoblastic differentiation transition in vitro. This study provides a theoretical basis for odontoblast differentiation and the formation of reparative dentine regeneration.
Characterization of the treatment-naive immune microenvironment in melanoma with <i>BRAF</i> mutation
Authors: Minyu Wang, Soroor Zadeh, Angela Pizzolla, Kevin Thia, David E Gyorki, Grant A McArthur, Richard A Scolyer, Georgina Long, James S Wilmott, Miles C Andrews, George Au-Yeung, Ali Weppler, Shahneen Sandhu, Joseph A Trapani, Melissa J Davis, Paul Joseph Neeson
Journal: Journal for ImmunoTherapy of Cancer (2022)

Background Patients with BRAF -mutant and wild-type melanoma have different response rates to immune checkpoint blockade therapy. However, the reasons for this remain unknown. To address this issue, we investigated the precise immune composition resulting from BRAF mutation in treatment-naive melanoma to determine whether this may be a driver for different response to immunotherapy. Methods In this study, we characterized the treatment-naive immune context in patients with BRAF -mutant and BRAF wild-type ( BRAF -wt) melanoma using data from single-cell RNA sequencing, bulk RNA sequencing, flow cytometry and immunohistochemistry (IHC). Results In single-cell data, BRAF -mutant melanoma displayed a significantly reduced infiltration of CD8 + T cells and macrophages but also increased B cells, natural killer (NK) cells and NKT cells. We then validated this finding using bulk RNA-seq data from the skin cutaneous melanoma cohort in The Cancer Genome Atlas and deconvoluted the data using seven different algorithms. Interestingly, BRAF -mutant tumors had more CD4 + T cells than BRAF -wt samples in both primary and metastatic cohorts. In the metastatic cohort, BRAF -mutant melanoma demonstrated more B cells but less CD8 + T cell infiltration when compared with BRAF -wt samples. In addition, we further investigated the immune cell infiltrate using flow cytometry and multiplex IHC techniques. We confirmed that BRAF -mutant melanoma metastases were enriched for CD4 + T cells and B cells and had a co-existing decrease in CD8 + T cells. Furthermore, we then identified B cells were associated with a trend for improved survival (p=0.078) in the BRAF -mutant samples and Th2 cells were associated with prolonged survival in the BRAF -wt samples. Conclusions In conclusion, treatment-naive BRAF -mutant melanoma has a distinct immune context compared with BRAF -wt melanoma, with significantly decreased CD8 + T cells and increased B cells and CD4 + T cells in the tumor microenvironment. These findings indicate that further mechanistic studies are warranted to reveal how this difference in immune context leads to improved outcome to combination immune checkpoint blockade in BRAF -mutant melanoma.
<i>Notes from the Field:</i> Wound Botulism Outbreak Among a Group of Persons Who Inject Drugs — Dallas, Texas, 2020
Authors: Leslie D. Edwards, Ivorry Gomez, Suzanne Wada, Erin M. Swaney, Michelle B. Caruthers, Irina Cody, Farrell A. Tobolowsky, Janet Dykes, Laura Ford, Kenneth R. Davis, Chelsey T. Griffin, Wendy Chung
Journal: MMWR Morbidity and Mortality Weekly Report (2022)
Telomere dysfunction implicates POT1 in patients with idiopathic pulmonary fibrosis
Authors: Joseph Kelich, Tomas Aramburu, Joanne J. van der Vis, Louise Showe, Andrew Kossenkov, Jasper van der Smagt, Maarten Massink, Angela Schoemaker, Eric Hennekam, Marcel Veltkamp, Coline H.M. van Moorsel, Emmanuel Skordalakes
Journal: The Journal of Experimental Medicine (2022)

Exonic sequencing identified a family with idiopathic pulmonary fibrosis (IPF) containing a previously unreported heterozygous mutation in POT1 p.(L259S). The family displays short telomeres and genetic anticipation. We found that POT1(L259S) is defective in binding the telomeric overhang, nuclear accumulation, negative regulation of telomerase, and lagging strand maintenance. Patient cells containing the mutation display telomere loss, lagging strand defects, telomere-induced DNA damage, and premature senescence with G1 arrest. Our data suggest POT1(L259S) is a pathogenic driver of IPF and provide insights into gene therapy options.
Autologous regulatory T-cell transfer in refractory ulcerative colitis with concomitant primary sclerosing cholangitis
Authors: Caroline Voskens, Diane Stoica, Marita Rosenberg, Francesco Vitali, Sebastian Zundler, Marion Ganslmayer, Heike Knott, Manuel Wiesinger, Jutta Wunder, Mirko Kummer, Britta Siegmund, Elisabeth Schnoy, Timo Rath, Arndt Hartmann, Holger Hackstein, Beatrice Schuler-Thurner, Carola Berking, Gerold Schuler, Raja Atreya, Markus F Neurath
Journal: Gut (2022)

Objective Ulcerative colitis (UC) is a chronic, debilitating immune-mediated disease driven by disturbed mucosal homeostasis, with an excess of intestinal effector T cells and an insufficient expansion of mucosal regulatory T cells (Tregs). We here report on the successful adoptive transfer of autologous, ex vivo expanded Tregs in a patient with refractory UC and associated primary sclerosing cholangitis (PSC), for which effective therapy is currently not available. Design The patient received a single infusion of 1×10 6 autologous, ex vivo expanded, polyclonal Tregs per kilogram of body weight, and the clinical, biochemical, endoscopic and histological responses were assessed 4 and 12 weeks after adoptive Treg transfer. Results The patient showed clinical, biochemical, endoscopic and histological signs of response until week 12 after adoptive Treg transfer, which was associated with an enrichment of intestinal CD3 + /FoxP3 + and CD3 + /IL-10 + T cells and increased mucosal transforming growth factor beta and amphiregulin levels. Moreover, there was marked improvement of PSC with reduction of liver enzymes. This pronounced effect lasted for 4 weeks before values started to increase again. Conclusion These findings suggest that adoptive Treg therapy might be effective in refractory UC and might open new avenues for clinical trials in PSC. Trial registration number NCT04691232 .