tbuckley/cabot-search huggingface dataset:
Melanoma Incidence Rates Among Non-Hispanic American Indian/Alaska Native Individuals, 1999-2019
Authors: Julie S. Townsend, Stephanie C. Melkonian, Melissa A. Jim, Dawn M. Holman, Melissa Buffalo, Anne K. Julian
Journal: JAMA Dermatology (2023)

Non-Hispanic American Indian/Alaska Native people have the second highest incidence rate of invasive cutaneous melanoma in the US after non-Hispanic White people.
Reply: Halting antiviral therapy in patients with cirrhosis and chronic hepatitis B: A dangerous game?
Authors: Wen-Juei Jeng, Rong-Nan Chien, Yun-Fan Liaw
Journal: Hepatology (2023)

The comments of Chen et al are similar to earlier letters, to which we have previously responded.1,2 They have additional questions probably because they missed/neglected relevant information in our study and our previous reply letters.1 (their reference 3). Hence, the mischievous wording "dangerous game" is groundless and inappropriate. The concern of "immortal time bias" was prevented by resetting "time 0" at end-of-treatment (finite group)/3-year-on-treatment (continued-group).3 Propensity score matching, the best second to "randomized controlled trials" (RCTs), is widely used in antiviral studies. While RCTs are highly valued, it would take > 5–10 more years from now for conclusive results. Given the current unsatisfactory status of drug development, our beneficial results are timely and crucial for strategic considerations in future efforts toward the ultimate therapeutic goal, including the reduction of HCC/mortality. Lost-to-follow-up (LTFU), self-discontinuation, and poor compliance are inherent risks during long-term therapy/follow-up.4 The poor outcomes of such patients were well documented in 6 continued-group and 3 finite-group patients. Excluding these patients from the calculation will fail to reflect the real situation and, hence, is inappropriate. Furthermore, a sensitivity analysis excluding LTFU/self-stop had been conducted and reached same conclusions ("per-protocol analysis" subsection, Supplementary Table 9 and Figure S4). Finite-group patients who were retreated were not censored but were compared with unretreated patients and continued-group patients (Figures 2B and 3B, Supplementary Tables S3 and S6). Regrettably, Chen et al wrongfully inflated the ACLF/hepatic decompensation death rate in the finite group. As detailed in Table 1 of our earlier reply the rate of the non-HCC liver–related death/liver transplantations, including the ACLF rate in the finite group, was not higher [7 (1.4%) vs. 16 (2.7%)].2 This rate in finite-group aligns with ~1% reported in a systematic review.5 Hence, deeming finite therapy a dangerous game is absolutely wrong. Indeed, the remarkable beneficial outcomes, including a >50% reduction of HCC/mortality and > 10-fold increase in HBsAg loss, surpass expectations. These findings from a meticulously conducted large study with extensive follow-up conclusively advocate for finite Nuc therapy with proper monitoring in compensated cirrhotic patients.
Letter to the Editor: Improving access to transient elastography data for real-world prognostic applications in primary biliary cholangitis
Authors: Johannes Wiegand, Annegret Franke, Kerstin Stein, Christian Trautwein, Thomas Berg
Journal: Hepatology (2023)

To the editor, With great interest, we read the article of Corpechot et al,1 who identify levels of alkaline phosphatase <1.0 × upper limit of normal during therapy with ursodeoxycholic acid as the ideal biochemical response. This is especially true for patients with liver stiffness measurement ≥ 10 kPa and/or age ≤ 62 years with a 10-year complication-free survival gain of more than four years. This article combines the relevance of biochemical response during ursodeoxycholic acid therapy with data on transient elastography (TE), which recently has been highlighted to be a valuable surrogate parameter of fibrosis and of major importance for the prediction of poor clinical outcomes in patients with PBC.2 These 2 landmark papers are likely to change indications for second-line therapies in clinical guidelines, which are so far based on biochemical response criteria only3 (Figure 1). Accessible and widespread implementation of TE in clinical routines will be crucial to optimally manage patients for better patient outcomes.FIGURE 1: Current und future risk stratification in patients with PBC: Availability of transient elastography is a challenge.The Corpechot data have been collected in highly selected patients recruited at tertiary referral centers upon the bias of at least 1 available liver stiffness measurement. In the real world, however, only a subgroup of patients with PBC has access to transient elastography: 34%, 53%, and 48% at university hospitals, non-university hospitals, and private practices at PBC diagnosis in France and Belgium,4 26% and 24% in patients receiving obeticholic acid and fibrates in Spain,5 respectively. In Germany, only about 140 TE devices are available. In the German PBC registry, TE data are reported in 304/496 (61%) individuals [249/345 (66%) vs. 75/151 (50%) at academic vs. non-academic centers]. In conclusion, addressing this challenge requires exploring strategies to broaden access to TE for more patients with PBC, enabling updated risk stratification, and timely initiation of second-line therapies. Additionally, developing alternative surrogate parameters for fibrosis staging in PBC will be important to ensure comprehensive patient care in real-world settings.
Impact of the Identification of Nonhuman Genetic Signatures in the Diagnosis and Management of Carcinoma of Unknown Primary
Authors: Arantzazu Barquín García, Sara Palacios-Zambrano, Felipe Lozano Alarcón, Beatriz Paumard-Hernández, Miguel Quiralte Pulido, Paloma Navarro, Laura Rodríguez, Isabel Salas Villar, Jesús García-Donas
Journal: Journal of the National Comprehensive Cancer Network (2023)

This report presents the case of a 62-year-old woman who was diagnosed in 1999 with stage I cervical carcinoma treated by surgical resection. In 2021, she presented to the emergency department with a complaint of predominantly right-sided lower back pain. A CT scan of the lumbosacral region revealed a bone lesion in the L5 vertebra and retroperitoneal lymphadenopathies suggestive of malignancy. Histology of the L5 vertebra biopsy showed a poorly differentiated carcinoma with an inconclusive immunophenotypic profile. Treatment for carcinoma of unknown primary was started with a combination of carboplatin and paclitaxel every 21 days. A genomic study of the biopsy specimen performed on the FoundationOne CDx platform identified a nonhuman genetic signature compatible with HPV. The presence of HPV 18 DNA in the specimen was confirmed by PCR-reverse dot blot, and the immunophenotypic profile was expanded, revealing strong and diffuse p16 expression, thus corroborating the molecular findings. In view of these findings, the case was reclassified as a recurrence of the cervical adenocarcinoma that had been diagnosed and treated 23 years earlier. Based on the new results, and according to first-line cervical carcinoma protocols, bevacizumab at 15 mg/kg every 21 days was added to her chemotherapy regimen. The identification of HPV DNA sequences by next-generation sequencing facilitated the correct diagnosis and led to a modification of the first-line therapeutic approach.
Associations Between Patient Experience With Care, Race and Ethnicity, and Receipt of CRC Treatment Among SEER-CAHPS Patients With Multiple Comorbidities
Authors: Stephanie Navarro, Jennifer Tsui, Afsaneh Barzi, Mariana C. Stern, Trevor Pickering, Albert J. Farias
Journal: Journal of the National Comprehensive Cancer Network (2023)

Background: Patients with colorectal cancer (CRC) and multiple comorbidities are less likely to receive guideline-concordant treatment (GCT), a disparity exacerbated by racial and ethnic disparities in GCT. Yet, positive patient experiences with care are associated with more appropriate care use. We investigated associations between patient experiences with care, race and ethnicity, and receipt of GCT for CRC among older adults with multiple comorbidities. Methods: We used SEER-Consumer Assessment of Healthcare Providers and Systems (CAHPS) data to identify participants diagnosed with CRC from 2001 to 2017 at age ≥67 years with additional chronic conditions. Stage-specific GCT was identified following recommendations in the NCCN Guidelines for Colon and Rectal Cancer. Patient experiences with care were identified from CAHPS surveys. Multivariable log-binomial regression estimated associations between race and ethnicity and receipt of GCT by experiences with care. Results: A total of 2,612 patients were included. Those reporting excellent experience with getting care quickly were 5% more likely to receive GCT than those reporting less-than-excellent experience (relative risk [RR], 1.05; 95% CI, 1.04–1.05). When reporting less-than-excellent experience with getting care quickly, non-Hispanic Black (NHB) patients were less likely than non-Hispanic White (NHW) patients to receive GCT (RR, 0.80; 99.38% CI, 0.78–0.82), yet NHB patients were more likely to receive GCT than NHW patients when reporting excellent experience (RR, 1.05; 99.38% CI, 1.02–1.09). When reporting less-than-excellent experience with getting needed care, Hispanic patients were less likely than NHW patients to receive GCT (RR, 0.91; 99.38% CI, 0.88–0.94), yet Hispanic patients were more likely to receive GCT than NHW patients when reporting excellent experience (RR, 1.06; 99.38% CI, 1.03–1.08). Conclusions: Although excellent patient experience among those with multiple comorbidities may not be strongly associated with receipt of GCT for CRC overall, improvements in experiences of accessing care among NHB and Hispanic patients with CRC and additional comorbidities may aid in mitigating racial and ethnic disparities in receipt of GCT.
Small-molecule inhibition of kinesin KIF18A reveals a mitotic vulnerability enriched in chromosomally unstable cancers
Authors: Marc Payton, Brian Belmontes, Kelly Hanestad, Jodi Moriguchi, Kui Chen, John D McCarter, Grace Chung, Maria Stefania Ninniri, Jan Sun, Raffi Manoukian, Stuart Chambers, Seok-Man Ho, Robert J M Kurzeja, Katheryne Z Edson, Upendra P Dahal, Tian Wu, Sharon Wannberg, Pedro J Beltran, Jude Canon, Andrew S Boghossian, Matthew G Rees, Melissa M Ronan, Jennifer A Roth, Sheroy Minocherhomji, Matthew P Bourbeau, Jennifer R Allen, Angela Coxon, Nuria A Tamayo, Paul E Hughes
Journal: Nature Cancer (2023)

Abstract Chromosomal instability (CIN) is a hallmark of cancer, caused by persistent errors in chromosome segregation during mitosis. Aggressive cancers like high-grade serous ovarian cancer (HGSOC) and triple-negative breast cancer (TNBC) have a high frequency of CIN and TP53 mutations. Here, we show that inhibitors of the KIF18A motor protein activate the mitotic checkpoint and selectively kill chromosomally unstable cancer cells. Sensitivity to KIF18A inhibition is enriched in TP53 -mutant HGSOC and TNBC cell lines with CIN features, including in a subset of CCNE1 -amplified, CDK4–CDK6-inhibitor-resistant and BRCA1 -altered cell line models. Our KIF18A inhibitors have minimal detrimental effects on human bone marrow cells in culture, distinct from other anti-mitotic agents. In mice, inhibition of KIF18A leads to robust anti-cancer effects with tumor regression observed in human HGSOC and TNBC models at well-tolerated doses. Collectively, our results provide a rational therapeutic strategy for selective targeting of CIN cancers via KIF18A inhibition.
Mechanical plaque removal in step‐1 of care
Authors: G. A. (Fridus) Van der Weijden, Cor van Loveren
Journal: Periodontology 2000 (2023)

Abstract Maintaining a regular oral hygiene routine is essential for taking care of our mouths, ensuring healthy teeth, and achieving fresh breath. Patient education on oral hygiene is an important component of their overall treatment. Firstly, patients should be informed about the direct connection between bacteria in dental plaque and oral diseases. It is important for patients to understand that these conditions can be treated, but the success of treatment greatly depends on their level of oral hygiene. This journey begins by selecting the appropriate toothbrush and mastering the correct brushing technique to effectively remove dental plaque while avoiding any potential damage to the gums. In addition to toothbrushes, there are other devices available for comprehensive dental cleaning, such as floss, interdental sticks, interdental brushes, and oral irrigators. These aids are particularly beneficial for eliminating dental plaque from hard‐to‐reach areas. Moreover, tongue brushing or tongue scraping can effectively reduce breath odor and tongue coating. Currently, self‐care recommendations for dental implants are primarily based on existing knowledge regarding natural teeth cleaning. Evidence‐based recommendations are derived from comprehensive systematic evaluation of various oral hygiene aids.
Microbial collaborations and conflicts: unraveling interactions in the gut ecosystem
Authors: Shuang Wang, Lingyi Mu, Chong Yu, Yuting He, Xinliang Hu, Yanlei Jiao, Ziqiong Xu, Shaohui You, Shu-Lin Liu, Hongxia Bao
Journal: Gut Microbes (2023)

The human gut microbiota constitutes a vast and complex community of microorganisms. The myriad of microorganisms present in the intestinal tract exhibits highly intricate interactions, which play a crucial role in maintaining the stability and balance of the gut microbial ecosystem. These interactions, in turn, influence the overall health of the host. The mammalian gut microbes have evolved a wide range of mechanisms to suppress or even eliminate their competitors for nutrients and space. Simultaneously, extensive cooperative interactions exist among different microbes to optimize resource utilization and enhance their own fitness. This review will focus on the competitive mechanisms among members of the gut microorganisms and discuss key modes of actions, including bacterial secretion systems, bacteriocins, membrane vesicles (MVs) etc. Additionally, we will summarize the current knowledge of the often-overlooked positive interactions within the gut microbiota, and showcase representative machineries. This information will serve as a reference for better understanding the complex interactions occurring within the mammalian gut environment. Understanding the interaction dynamics of competition and cooperation within the gut microbiota is crucial to unraveling the ecology of the mammalian gut microbial communities. Targeted interventions aimed at modulating these interactions may offer potential therapeutic strategies for disease conditions.
Towards in vitro models for reducing or replacing the use of animals in drug testing
Authors: David M Stresser, Anna K Kopec, Philip Hewitt, Rhiannon N Hardwick, Terry R Van Vleet, Prathap Kumar S Mahalingaiah, Denice O'Connell, Gary J Jenkins, Rhiannon David, Jessica Graham, Donna Lee, Jason Ekert, Aaron Fullerton, Remi Villenave, Piyush Bajaj, James R Gosset, Sherry L Ralston, Manti Guha, Alejandro Amador-Arjona, Kainat Khan, Saket Agarwal, Catrin Hasselgren, Xiaoting Wang, Khary Adams, Gaurav Kaushik, Arkadiusz Raczynski, Kimberly A Homan
Journal: Nature Biomedical Engineering (2023)
Colicins and T6SS-based competition systems enhance enterotoxigenic <i>E. coli</i> (ETEC) competitiveness
Authors: Jonas Kjellin, Danna Lee, Hans Steinsland, Rachel Dwane, Oda Barth Vedoy, Kurt Hanevik, Sanna Koskiniemi
Journal: Gut Microbes (2023)

Diarrheal diseases are still a significant problem for humankind, causing approximately half a million deaths annually. To cause diarrhea, enteric bacterial pathogens must first colonize the gut, which is a niche occupied by the normal bacterial microbiota. Therefore, the ability of pathogenic bacteria to inhibit the growth of other bacteria can facilitate the colonization process. Although enterotoxigenic Escherichia coli (ETEC) is one of the major causative agents of diarrheal diseases, little is known about the competition systems found in and used by ETEC and how they contribute to the ability of ETEC to colonize a host. Here, we collected a set of 94 fully assembled ETEC genomes by performing whole-genome sequencing and mining the NCBI RefSeq database. Using this set, we performed a comprehensive search for delivered bacterial toxins and investigated how these toxins contribute to ETEC competitiveness in vitro. We found that type VI secretion systems (T6SS) were widespread among ETEC (n = 47). In addition, several closely related ETEC strains were found to encode Colicin Ia and T6SS (n = 8). These toxins provide ETEC competitive advantages during in vitro competition against other E. coli, suggesting that the role of T6SS as well as colicins in ETEC biology has until now been underappreciated.
Impact of Recombinant Granulocyte Colony-Stimulating Factor During Neoadjuvant Therapy on Outcomes of Resected Pancreatic Cancer
Authors: Pranav Murthy, Mazen S. Zenati, Samer S. AlMasri, Annissa DeSilva, Aatur D. Singhi, Alessandro Paniccia, Kenneth K. Lee, Richard L. Simmons, Nathan Bahary, Michael T. Lotze, Amer H. Zureikat
Journal: Journal of the National Comprehensive Cancer Network (2023)

Pancreatic ductal adenocarcinoma (PDAC) is an aggressive disease characterized by chronic inflammation and a tolerogenic immune response. The granulocyte colony-stimulating factor (G-CSF)-neutrophil axis promotes oncogenesis and progression of PDAC. Despite frequent use of recombinant G-CSF in the management and prevention of chemotherapy-induced neutropenia, its impact on oncologic outcomes of patients with resected PDAC is unclear.
Acute Lymphoblastic Leukemia with Myeloid Mutations Is a High-Risk Disease Associated with Clonal Hematopoiesis
Authors: Caner Saygin, Pu Zhang, Jacob Stauber, Ibrahim Aldoss, Adam S. Sperling, Lachelle D. Weeks, Marlise R. Luskin, Todd C. Knepper, Pankhuri Wanjari, Peng Wang, Angela M. Lager, Carrie Fitzpatrick, Jeremy P. Segal, Mehdi Gharghabi, Sandeep Gurbuxani, Girish Venkataraman, Jason X. Cheng, Bart J. Eisfelder, Oliver Bohorquez, Anand A. Patel, Sheethal Umesh Nagalakshmi, Savita Jayaram, Olatoyosi M. Odenike, Richard A. Larson, Lucy A. Godley, Daniel A. Arber, Christopher J. Gibson, Nikhil C. Munshi, Guido Marcucci, Benjamin L. Ebert, John M. Greally, Ulrich Steidl, Rosa Lapalombella, Bijal D. Shah, Wendy Stock
Journal: Blood Cancer Discovery (2023)

Abstract Myeloid neoplasms arise from preexisting clonal hematopoiesis (CH); however, the role of CH in the pathogenesis of acute lymphoblastic leukemia (ALL) is unknown. We found that 18% of adult ALL cases harbored TP53, and 16% had myeloid CH-associated gene mutations. ALL with myeloid mutations (MyM) had distinct genetic and clinical characteristics, associated with inferior survival. By using single-cell proteogenomic analysis, we demonstrated that myeloid mutations were present years before the diagnosis of ALL, and a subset of these clones expanded over time to manifest as dominant clones in ALL. Single-cell RNA sequencing revealed upregulation of genes associated with cell survival and resistance to apoptosis in B-ALL with MyM, which responds better to newer immunotherapeutic approaches. These findings define ALL with MyM as a high-risk disease that can arise from antecedent CH and offer new mechanistic insights to develop better therapeutic and preventative strategies. Significance: CH is a precursor lesion for lymphoblastic leukemogenesis. ALL with MyM has distinct genetic and clinical characteristics, associated with adverse survival outcomes after chemotherapy. CH can precede ALL years before diagnosis, and ALL with MyM is enriched with activated T cells that respond to immunotherapies such as blinatumomab. See related commentary by Iacobucci, p. 142.
Letter to the Editor: Halting antiviral therapy in patients with cirrhosis and chronic hepatitis B: A dangerous game?
Authors: Jacki Chen, Thomas Tu, Chari Cohen, Su Wang, Yao-Chun Hsu, Robert G. Gish
Journal: Hepatology (2023)

To the editor, When Jeng et al1 reported that stopping antivirals in patients with cirrhosis and chronic hepatitis B had better outcomes than continuing therapy, debate followed.2,3 Similarly, we are concerned with several issues that affect the interpretation of this study. First, the study groups were not likely to be comparable despite the sophisticated statistical methods. For example, patients were not assigned randomly, but instead by patient/physician preferences, allowing those with healthier baseline characteristics, like platelet count, fibrosis-4 score, and viral load, to be clustered in the finite group. Initiating outcome observation after a fixed treatment duration in the continuous group, while allowing variable treatment times in the finite group, introduced an "immortal time" bias. To mitigate these potential biases, retreated patients should have been followed after retreatment instead of after treatment cessation.4 In addition, Taiwan's national health insurance policy mandated portal hypertension (eg, esophagogastric varices or splenomegaly) as a requirement for continuous treatment.5 To address potential selection bias, the distribution of patients with portal hypertension between the 2 study groups should be reported. Second, a significant proportion of deaths (40%) in the continuous group were due to loss to follow-up, self-discontinuation, or poor compliance with medication. Those deaths should be censored and not included as treatment-related outcomes. Patients who actually discontinued treatment should not be part of the continuous group. Moreover, the study population was not all treatment-naïve. A substantial portion of the patients had started and then stopped antiviral therapy without occurrences of the study outcomes before "the start of treatment" reported in the analysis. In the finite group, a notable percentage of deaths (44%) occurred due to acute-on-chronic liver failure or hepatic decompensation after treatment cessation. These events were rare in the continuous group except upon self-discontinuation of medication, emphasizing why stopping therapy is high risk in this cohort and has not been the standard of care.5 These severe adverse outcomes from treatment cessation should have been factored into the analysis. The potential benefits of viral reactivation in antiviral immunity warrant further investigation; however, encouraging discontinuation of antiviral therapy in patients with cirrhosis and chronic hepatitis B carries ethical and potentially dangerous implications.
Distinct clinico-molecular arterial and venous thrombosis scores for myeloproliferative neoplasms risk stratification
Authors: Hélène Pasquer, Rafael Daltro de Oliveira, Loic Vasseur, Juliette Soret-Dulphy, Nabih Maslah, Lin-Pierre Zhao, Clémence Marcault, Marine Cazaux, Nicolas Gauthier, Emmanuelle Verger, Nathalie Parquet, William Vainchenker, Emmanuel Raffoux, Valérie Ugo, Damien Luque Paz, Lydia Roy, Wayne-Corentin Lambert, Jean-Christophe Ianotto, Eric Lippert, Stéphane Giraudier, Bruno Cassinat, Jean-Jacques Kiladjian, Lina Benajiba
Journal: Leukemia (2023)