tbuckley/cabot-search huggingface dataset:
Near‐Infrared‐Enpowered Nanomotor‐Mediated Targeted Chemotherapy and Mitochondrial Phototherapy to Boost Systematic Antitumor Immunity
Authors: Xueqing Zhang, Qian He, Jianfeng Sun, Hanlin Gong, Yingui Cao, Lian Duan, Shixiong Yi, Binwu Ying, Bo Xiao
Journal: Advanced Healthcare Materials (2022)

Phototherapy is an important strategy to inhibit tumor growth and activate antitumor immunity. However, the effect of photothermal/photodynamic therapy (PTT/PDT) is restricted by limited tumor penetration depth and unsatisfactory potentiation of antitumor immunity. Here, a near-infrared (NIR)-driven nanomotor is constructed with a mesoporous silicon nanoparticle (MSN) as the core, end-capped with Antheraea pernyi silk fibroin (ApSF) comprising arginine-glycine-aspartate (RGD) tripeptides. Upon NIR irradiation, the resulting ApSF-coated MSNs (DIMs) loading with photosensitizers (ICG derivatives, IDs) and chemotherapeutic drugs (doxorubicin, Dox) can efficiently penetrate into the internal tumor tissues and achieve effective phototherapy. Combined with chemotherapy, a triple-modal treatment (PTT, PDT, and chemotherapy) approach is developed to induce the immunogenic cell death of tumor cells and to accelerate the release of damage-associated molecular patterns. In vivo results suggest that DIMs can promote the maturation of dendritic cells and surge the number of infiltrated immune cells. Meanwhile, DIMs can polarize macrophages from M2 to M1 phenotypes and reduce the percentages of immunosuppressive Tregs, which reverse the immunosuppressive tumor microenvironment and activate systemic antitumor immunity. By achieving synergistic effects on the tumor inhibition and the antitumor immunity activation, DIMs show great promise as new nanoplatforms to treat metastatic breast cancer.
The COVID-19 Pandemic and Racial and Ethnic Disparities in Estimated Excess Mortality From External Causes
Authors: Irving Ling, Mithi Del Rosario, Cary P. Gross
Journal: JAMA Internal Medicine (2022)

Ruijia Chen, ScD; Hélène E. Aschmann, PhD; Yea-Hung Chen, PhD; M. Maria Glymour, ScD; Kirsten Bibbins-Domingo, MD; Andrew C. Stokes, PhD; Mathew V. Kiang, ScD
Patient-Derived Triple-Negative Breast Cancer Organoids Provide Robust Model Systems That Recapitulate Tumor Intrinsic Characteristics
Authors: Sonam Bhatia, Melissa Kramer, Suzanne Russo, Payal Naik, Gayatri Arun, Kyle Brophy, Peter Andrews, Cheng Fan, Charles M. Perou, Jonathan Preall, Taehoon Ha, Dennis Plenker, David A. Tuveson, Arvind Rishi, John E. Wilkinson, W. Richard McCombie, Karen Kostroff, David L. Spector
Journal: Cancer Research (2022)

Abstract Triple-negative breast cancer (TNBC) is an aggressive form of breast cancer with poor patient outcomes, highlighting the unmet clinical need for targeted therapies and better model systems. Here, we developed and comprehensively characterized a diverse biobank of normal and breast cancer patient-derived organoids (PDO) with a focus on TNBCs. PDOs recapitulated patient tumor intrinsic properties and a subset of PDOs can be propagated for long-term culture (LT-TNBC). Single cell profiling of PDOs identified cell types and gene candidates affiliated with different aspects of cancer progression. The LT-TNBC organoids exhibit signatures of aggressive MYC-driven, basal-like breast cancers and are largely comprised of luminal progenitor (LP)-like cells. The TNBC LP-like cells are distinct from normal LPs and exhibit hyperactivation of NOTCH and MYC signaling. Overall, this study validates TNBC PDOs as robust models for understanding breast cancer biology and progression, paving the way for personalized medicine and tailored treatment options. Significance: A comprehensive analysis of patient-derived organoids of TNBC provides insights into cellular heterogeneity and mechanisms of tumorigenesis at the single-cell level.
Author Correction: The International Scientific Association of Probiotics and Prebiotics (ISAPP) consensus statement on the definition and scope of postbiotics
Authors: Seppo Salminen, Maria Carmen Collado, Akihito Endo, Colin Hill, Sarah Lebeer, Eamonn M. M. Quigley, Mary Ellen Sanders, Raanan Shamir, Jonathan R. Swann, Hania Szajewska, Gabriel Vinderola
Journal: Nature Reviews Gastroenterology & Hepatology (2022)
Farm-level production diversity and child and adolescent nutrition in rural sub-Saharan Africa: a multicountry, longitudinal study
Authors: Makaiko G Khonje, Jacob Ricker-Gilbert, Milu Muyanga, Matin Qaim
Journal: The Lancet Planetary Health (2022)

Child malnutrition remains widespread in sub-Saharan Africa, especially in rural areas where many households are involved in subsistence farming. Increasing farm-level production diversity (FPD) is often considered a useful strategy to improve child diets and nutrition, but the empirical evidence is mixed. Most studies have investigated associations between FPD and dietary diversity. We therefore aimed to analyse associations between FPD and child and adolescent nutritional status.In this multicountry, longitudinal study, we used representative panel data from four countries in sub-Saharan Africa (Ethiopia, Malawi, Tanzania, and Uganda) to test the hypothesis that higher FPD is positively associated with child and adolescent nutritional status. The data were from the Living Standards Measurement Study-Integrated Surveys on Agriculture collected between 2008 and 2019. We included data from all children and adolescents aged 0-18 years with available anthropometric data who were living in households involved in farming activities for home consumption, market sales, or both. FPD was measured in terms of the number of different crop and livestock species and food groups produced on each farm. Child and adolescent nutritional status was measured in terms of height-for-age Z scores (HAZ). We estimated panel data regression models with correlated random effects to control for confounding factors and time-invariant unobserved heterogeneity.The total sample size included 50 689 child and adolescent observations. In combined models, with data from all countries included, we found one additional species produced on the farm (crop and livestock combined) was associated with a mean 0·015 SD greater child or adolescent HAZ (p<0·0001). The role of FPD tended to decrease with better market access (in more remote locations mean 0·020 SD [p<0·0001] and in less remote locations mean 0·008 SD [p=0·091]). In individual-country models, the effects were smaller and statistically insignificant in three of the four countries. Livestock diversity had larger positive associations with HAZ than crop diversity (livestock diversity effect on HAZ mean 0·085 SD [p<0·0001] and crop diversity effect on HAZ mean 0·007 SD [p=0·080]). In Tanzania and Uganda, higher crop diversity was negatively associated with child and adolescent HAZ.Our findings suggest that further farm-level diversification is not a suitable general strategy to improve child and adolescent nutrition but might be useful in some situations. Livestock production seems to be conducive for improving child and adolescent nutrition on average. Context-specific approaches need to be developed.None.
Fourth Dose of BNT162b2 mRNA Covid-19 Vaccine in a Nationwide Setting
Authors: Ori Magen, Jacob G. Waxman, Maya Makov-Assif, Roni Vered, Dror Dicker, Miguel A. Hernán, Marc Lipsitch, Ben Y. Reis, Ran D. Balicer, Noa Dagan
Journal: New England Journal of Medicine (2022)

With large waves of infection driven by the B.1.1.529 (omicron) variant of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), alongside evidence of waning immunity after the booster dose of coronavirus disease 2019 (Covid-19) vaccine, several countries have begun giving at-risk persons a fourth vaccine dose.To evaluate the early effectiveness of a fourth dose of the BNT162b2 vaccine for the prevention of Covid-19-related outcomes, we analyzed data recorded by the largest health care organization in Israel from January 3 to February 18, 2022. We evaluated the relative effectiveness of a fourth vaccine dose as compared with that of a third dose given at least 4 months earlier among persons 60 years of age or older. We compared outcomes in persons who had received a fourth dose with those in persons who had not, individually matching persons from these two groups with respect to multiple sociodemographic and clinical variables. A sensitivity analysis was performed with the use of parametric Poisson regression.The primary analysis included 182,122 matched pairs. Relative vaccine effectiveness in days 7 to 30 after the fourth dose was estimated to be 45% (95% confidence interval [CI], 44 to 47) against polymerase-chain-reaction-confirmed SARS-CoV-2 infection, 55% (95% CI, 53 to 58) against symptomatic Covid-19, 68% (95% CI, 59 to 74) against Covid-19-related hospitalization, 62% (95% CI, 50 to 74) against severe Covid-19, and 74% (95% CI, 50 to 90) against Covid-19-related death. The corresponding estimates in days 14 to 30 after the fourth dose were 52% (95% CI, 49 to 54), 61% (95% CI, 58 to 64), 72% (95% CI, 63 to 79), 64% (95% CI, 48 to 77), and 76% (95% CI, 48 to 91). In days 7 to 30 after a fourth vaccine dose, the difference in the absolute risk (three doses vs. four doses) was 180.1 cases per 100,000 persons (95% CI, 142.8 to 211.9) for Covid-19-related hospitalization and 68.8 cases per 100,000 persons (95% CI, 48.5 to 91.9) for severe Covid-19. In sensitivity analyses, estimates of relative effectiveness against documented infection were similar to those in the primary analysis.A fourth dose of the BNT162b2 vaccine was effective in reducing the short-term risk of Covid-19-related outcomes among persons who had received a third dose at least 4 months earlier. (Funded by the Ivan and Francesca Berkowitz Family Living Laboratory Collaboration at Harvard Medical School and Clalit Research Institute.).
Hypoxia-Reoxygenation Couples 3βHSD1 Enzyme and Cofactor Upregulation to Facilitate Androgen Biosynthesis and Hormone Therapy Resistance in Prostate Cancer
Authors: Liang Qin, Yoon-Mi Chung, Michael Berk, Bryan Naelitz, Ziqi Zhu, Eric Klein, Abhishek A. Chakraborty, Nima Sharifi
Journal: Cancer Research (2022)

Abstract Androgen deprivation therapy suppresses tumor androgen receptor (AR) signaling by depleting circulating testosterone and is a mainstay treatment for advanced prostate cancer. Despite initial treatment response, castration-resistant prostate cancer nearly always develops and remains driven primarily by the androgen axis. Here we investigated how changes in oxygenation affect androgen synthesis. In prostate cancer cells, chronic hypoxia coupled to reoxygenation resulted in efficient metabolism of androgen precursors to produce androgens and activate AR. Hypoxia induced 3βHSD1, the rate-limiting androgen synthesis regulator, and reoxygenation replenished necessary cofactors, suggesting that hypoxia and reoxygenation both facilitate potent androgen synthesis. The EGLN1/VHL/HIF2α pathway induced 3βHSD1 expression through direct binding of HIF2α to the 5′ regulatory region of HSD3B1 to promote transcription. Overexpression of HIF2α facilitated prostate cancer progression, which largely depended on 3βHSD1. Inhibition of HIF2α with the small-molecule PT2399 prevented prostate cancer cell proliferation. These results thus identify HIF2α as a regulator of androgen synthesis and potential therapeutic target in prostate cancer. Significance: Hypoxia followed by reoxygenation in prostate cancer drives androgen deprivation therapy resistance via increasing the rate-limiting enzyme and cofactors for androgen synthesis, revealing HIF2α as a therapeutic target to subvert resistance.
Patch testing with glucosides: The North American Contact Dermatitis Group experience, 2009-2018
Authors: Erin M. Warshaw, Michelle Xiong, Amber R. Atwater, Joel G. DeKoven, Melanie D. Pratt, Howard I. Maibach, James S. Taylor, Donald V. Belsito, Jonathan I. Silverberg, Margo J. Reeder, Kathryn A. Zug, Denis Sasseville, Joseph F. Fowler, Vincent A. DeLeo, Marie-Claude Houle, Cory A. Dunnick
Journal: Journal of the American Academy of Dermatology (2022)
Comparison of Survival Among Adults With Rectal Cancer Who Have Undergone Laparoscopic vs Open Surgery
Authors: Meng Kong, Hongyuan Chen, Keshu Shan, Hongguang Sheng, Leping Li
Journal: JAMA Network Open (2022)

<h3>Importance</h3> Two large randomized clinical trials (RCTs) found that laparoscopic surgery failed to yield noninferior pathologic outcomes compared with open surgery for patients with rectal cancer. The results raised concerns regarding the effectiveness of the laparoscopic approach for patients with rectal cancer. <h3>Objective</h3> To compare the long-term oncologic outcomes of laparoscopic and open surgery for patients with rectal cancer. <h3>Data Sources</h3> PubMed, Web of Science, Embase, and Cochrane Central Register of Controlled Trials were searched from database inception to August 13, 2021. Studies published in English were retrieved. <h3>Study Selection</h3> The meta-analysis included RCTs that compared laparoscopic surgery with open surgery for patients with rectal cancer and reported the outcome of disease-free survival (DFS) or overall survival (OS). The following exclusion criteria were used: (1) non-RCTs, (2) studies without long-term survival outcomes of interest, and (3) studies that did not report Kaplan-Meier survival curves. <h3>Data Extraction and Synthesis</h3> This meta-analysis was performed in line with the Preferred Reporting Items for Systematic Reviews and Meta-analyses reporting guideline for individual participant data development groups. Individual participant data on DFS and OS were extracted from the published Kaplan-Meier survival curves. One-stage and 2-stage meta-analyses were performed. <h3>Main Outcomes and Measures</h3> Meta-analyses were conducted for DFS and OS. Hazard ratios (HRs) were used as effective measures. <h3>Results</h3> Of 8471 records screened, 10 articles with 12 RCTs and 3709 participants were selected. The reconstructed survival curves for the combined population showed that the 5-year estimated DFS rates were 72.2% (95% CI, 69.4%-74.8%) for the laparoscopic group and 70.1% (95% CI, 67.0%-73.0%) for the open surgery group, and the 5-year estimated OS rates were 76.2% (95% CI, 73.8%-78.5%) for the laparoscopic group and 72.7% (95% CI, 69.8%-75.3%) for open surgery group. In 1-stage meta-analyses, DFS had a nonsignificant HR of 0.92 (95% CI, 0.80-1.06;<i>P</i> = .26), which suggested that DFS in the laparoscopic and open surgery groups was comparable; however, OS was significantly better in the laparoscopic group (HR, 0.85; 95% CI, 0.74-0.97;<i>P</i> = .02). The results were confirmed by 2-stage meta-analyses and were validated by sensitivity analysis with large RCTs. <h3>Conclusions and Relevance</h3> A similar DFS but significantly better OS were found for patients who have undergone laparoscopic surgery compared with open surgery for rectal cancer. These findings address concerns regarding the effectiveness of laparoscopic surgery and support the routine use of laparoscopic surgery for patients with rectal cancer.
Response by Nagareddy and Sreejit to Letter Regarding Article, “Retention of the NLRP3 Inflammasome-Primed Neutrophils in the Bone Marrow Is Essential for Myocardial Infarction–Induced Granulopoiesis”
Authors: Prabhakara R. Nagareddy, Gopalkrishna Sreejit
Journal: Circulation (2022)
A reactive oxygen species-responsive hydrogel encapsulated with bone marrow derived stem cells promotes repair and regeneration of spinal cord injury
Authors: Ziming Li, Tengfei Zhao, Jie Ding, Haochen Gu, Qiaoxuan Wang, Yifan Wang, Deteng Zhang, Changyou Gao
Journal: Bioactive Materials (2022)

Spinal cord injury (SCI) is an overwhelming and incurable disabling event accompanied by complicated inflammation-related pathological processes, such as excessive reactive oxygen species (ROS) produced by the infiltrated inflammatory immune cells and released to the extracellular microenvironment, leading to the widespread apoptosis of the neuron cells, glial and oligodendroctyes. In this study, a thioketal-containing and ROS-scavenging hydrogel was prepared for encapsulation of the bone marrow derived mesenchymal stem cells (BMSCs), which promoted the neurogenesis and axon regeneration by scavenging the overproduced ROS and re-building a regenerative microenvironment. The hydrogel could effectively encapsulate BMSCs, and played a remarkable neuroprotective role in vivo by reducing the production of endogenous ROS, attenuating ROS-mediated oxidative damage and downregulating the inflammatory cytokines such as interleukin-1 beta (IL-1β), interleukin-6 (IL-6) and tumor necrosis factor-alpha (TNF-α), resulting in a reduced cell apoptosis in the spinal cord tissue. The BMSCs-encapsulated ROS-scavenging hydrogel also reduced the scar formation, and improved the neurogenesis of the spinal cord tissue, and thus distinctly enhanced the motor functional recovery of SCI rats. Our work provides a combinational strategy against ROS-mediated oxidative stress, with potential applications not only in SCI, but also in other central nervous system diseases with similar pathological conditions.
The Cell Type–Specific 5hmC Landscape and Dynamics of Healthy Human Hematopoiesis and <i>TET2</i>-Mutant Preleukemia
Authors: Yusuke Nakauchi, Armon Azizi, Daniel Thomas, M. Ryan Corces, Andreas Reinisch, Rajiv Sharma, David Cruz Hernandez, Thomas Köhnke, Daiki Karigane, Amy Fan, Daniel Martinez-Krams, Melissa Stafford, Satinder Kaur, Ritika Dutta, Paul Phan, Asiri Ediriwickrema, Erin McCarthy, Yuhong Ning, Tierney Phillips, Christopher K. Ellison, Gulfem D. Guler, Anna Bergamaschi, Chin-Jen Ku, Samuel Levy, Ravindra Majeti
Journal: Blood Cancer Discovery (2022)

The conversion of 5-methylcytosine (5mC) to 5-hydroxymethylcytosine (5hmC) is a key step in DNA demethylation that is mediated by ten-eleven translocation (TET) enzymes, which require ascorbate/vitamin C. Here, we report the 5hmC landscape of normal hematopoiesis and identify cell type-specific 5hmC profiles associated with active transcription and chromatin accessibility of key hematopoietic regulators. We utilized CRISPR/Cas9 to model TET2 loss-of-function mutations in primary human hematopoietic stem and progenitor cells (HSPC). Disrupted cells exhibited increased colonies in serial replating, defective erythroid/megakaryocytic differentiation, and in vivo competitive advantage and myeloid skewing coupled with reduction of 5hmC at erythroid-associated gene loci. Azacitidine and ascorbate restored 5hmC abundance and slowed or reverted the expansion of TET2-mutant clones in vivo. These results demonstrate the key role of 5hmC in normal hematopoiesis and TET2-mutant phenotypes and raise the possibility of utilizing these agents to further our understanding of preleukemia and clonal hematopoiesis.
Trends in Colorectal Surgery During the COVID-19 Pandemic
Authors: Michael R. Freund, Steven D. Wexner
Journal: JAMA Network Open (2022)

Karolina Eklöv, MD; Jonas Nygren, MD; Sven Bringman, MD; Jenny Löfgren, MD; Annika Sjövall, MD; Caroline Nordenvall, MD; Åsa H. Everhov, MD
Attributable Mortality of Ventilator-associated Pneumonia Among Patients with COVID-19
Authors: Charles-Hervé Vacheron, Alain Lepape, Anne Savey, Anaïs Machut, Jean Francois Timsit, Sylvie Comparot, Gaelle Courno, Philippe Vanhems, Verena Landel, Thierry Lavigne, Sebastien Bailly, Francois Bettega, Delphine Maucort-Boulch, Arnaud Friggeri
Journal: American Journal of Respiratory and Critical Care Medicine (2022)

Rationale: Patients with a severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection are at higher risk of ventilator-associated pneumonia (VAP) and may have an increased attributable mortality (increased or decreased risk of death if VAP occurs in a patient) and attributable fraction (proportion of deaths that are attributable to an exposure) of VAP-related mortality compared with subjects without coronavirus disease (COVID-19). Objectives: Estimation of the attributable mortality of the VAP among patients with COVID-19. Methods: Using the REA-REZO surveillance network, three groups of adult medical ICU patients were computed: control group (patients admitted between 2016 and 2019; prepandemic patients), pandemic COVID-19 group (PandeCOV+), and pandemic non-COVID-19 group (PandeCOV-) admitted during 2020. The primary outcome was the estimation of attributable mortality and attributable fraction related to VAP in these patients. Using multistate modeling with causal inference, the outcomes related to VAP were also evaluated. Measurements and Main Results: A total of 64,816 patients were included in the control group, 7,442 in the PandeCOV- group, and 1,687 in the PandeCOV+ group. The incidence of VAP was 14.2 (95% confidence interval [CI], 13.9 to 14.6), 18.3 (95% CI, 17.3 to 19.4), and 31.9 (95% CI, 29.8 to 34.2) per 1,000 ventilation-days in each group, respectively. Attributable mortality at 90 days was 3.15% (95%, CI, 2.04% to 3.43%), 2.91% (95% CI, -0.21% to 5.02%), and 8.13% (95% CI, 3.54% to 12.24%), and attributable fraction of mortality at 90 days was 1.22% (95% CI, 0.83 to 1.63), 1.42% (95% CI, -0.11% to 2.61%), and 9.17% (95% CI, 3.54% to 12.24%) for the control, PandeCOV-, and PandeCOV+ groups, respectively. Except for the higher risk of developing VAP, the PandeCOV- group shared similar VAP characteristics with the control group. PandeCOV+ patients were at lower risk of death without VAP (hazard ratio, 0.62; 95% CI, 0.52 to 0.74) than the control group. Conclusions: VAP-attributable mortality was higher for patients with COVID-19, with more than 9% of the overall mortality related to VAP.