Intracytoplasmic sperm injection induces transgenerational abnormalities in mice
In vitro fertilization (IVF) and intracytoplasmic sperm injection (ICSI) are 2 major assisted reproductive techniques (ARTs) used widely to treat infertility. Recently, spermatogonial transplantation emerged as a new ART to restore fertility to young patients with cancer after cancer therapy. To examine the influence of germ cell manipulation on behavior of offspring, we produced F1 offspring by a combination of two ARTs, spermatogonial transplantation and ICSI. When these animals were compared with F1 offspring produced by ICSI using fresh wild-type sperm, not only spermatogonial transplantation–ICSI mice but also ICSI-...
Source: Journal of Clinical Investigation - November 15, 2023 Category: Biomedical Science Authors: Mito Kanatsu-Shinohara, Yusuke Shiromoto, Narumi Ogonuki, Kimiko Inoue, Satoko Hattori, Kento Miura, Naomi Watanabe, Ayumi Hasegawa, Keiji Mochida, Takuya Yamamoto, Tsuyoshi Miyakawa, Atsuo Ogura, Takashi Shinohara Source Type: research
Tumor-derived biomarkers predict efficacy of B7H3 antibody-drug conjugate treatment in metastatic prostate cancer models
We present a comprehensive therapeutic and biomarker analysis of a B7H3-ADC with pyrrolobenzodiazepine(PBD) payload in 26 treatment-resistant, metastatic prostate cancer (mPC) models. B7H3 is a tumor-specific surface protein widely expressed in mPC, and PBD is a DNA cross–linking agent. B7H3 expression was necessary but not sufficient for B7H3-PBD-ADC responsiveness. RB1 deficiency and/or replication stress, characteristics of poor prognosis, and conferred sensitivity were associated with complete tumor regression in both neuroendocrine (NEPC) and androgen receptor positive (ARPC) prostate cancer models, even with low B7...
Source: Journal of Clinical Investigation - November 15, 2023 Category: Biomedical Science Authors: Supreet Agarwal, Lei Fang, Kerry McGowen, JuanJuan Yin, Joel Bowman, Anson T. Ku, Aian Neil Alilin, Eva Corey, Martine P. Roudier, Lawrence D. True, Ruth Dumpit, Ilsa Coleman, John K. Lee, Peter S. Nelson, Brian J. Capaldo, Aida Mariani, Clare Hoover, Ily Source Type: research
A paracrine circuit of IL-1β/IL-1R1 between myeloid and tumor cells drives genotype-dependent glioblastoma progression
Monocytes and monocyte-derived macrophages (MDMs) from blood circulation infiltrate glioblastoma (GBM) and promote growth. Here, we show that PDGFB-driven GBM cells induce the expression of the potent proinflammatory cytokine IL-1β in MDM, which engages IL-1R1 in tumor cells, activates the NF-κB pathway, and subsequently leads to induction of monocyte chemoattractant proteins (MCPs). Thus, a feedforward paracrine circuit of IL-1β/IL-1R1 between tumors and MDM creates an interdependence driving PDGFB-driven GBM progression. Genetic loss or locally antagonizing IL-1β/IL-1R1 leads to reduced MDM infiltration, diminished t...
Source: Journal of Clinical Investigation - November 15, 2023 Category: Biomedical Science Authors: Zhihong Chen, Bruno Giotti, Milota Kaluzova, Montse Puigdelloses Vallcorba, Kavita Rawat, Gabrielle Price, Cameron J. Herting, Gonzalo Pinero, Simona Cristea, James L. Ross, James Ackley, Victor Maximov, Frank Szulzewsky, Wes Thomason, Mar Marquez-Ropero, Source Type: research
FXYD3 functionally demarcates an ancestral breast cancer stem cell subpopulation with features of drug-tolerant persisters
The heterogeneity of cancer stem cells (CSCs) within tumors presents a challenge in therapeutic targeting. To decipher the cellular plasticity that fuels phenotypic heterogeneity, we undertook single-cell transcriptomics analysis in triple-negative breast cancer (TNBC) to identify subpopulations in CSCs. We found a subpopulation of CSCs with ancestral features that is marked by FXYD domain–containing ion transport regulator 3 (FXYD3), a component of the Na+/K+ pump. Accordingly, FXYD3+ CSCs evolve and proliferate, while displaying traits of alveolar progenitors that are normally induced during pregnancy. Clinically, FXYD...
Source: Journal of Clinical Investigation - November 15, 2023 Category: Biomedical Science Authors: Mengjiao Li, Tatsunori Nishimura, Yasuto Takeuchi, Tsunaki Hongu, Yuming Wang, Daisuke Shiokawa, Kang Wang, Haruka Hirose, Asako Sasahara, Masao Yano, Satoko Ishikawa, Masafumi Inokuchi, Tetsuo Ota, Masahiko Tanabe, Kei-ichiro Tada, Tetsu Akiyama, Xi Chen Source Type: research
Hyperphosphorylation of BCL-2 family proteins underlies functional resistance to venetoclax in lymphoid malignancies
The B cell leukemia/lymphoma 2 (BCL-2) inhibitor venetoclax is effective in chronic lymphocytic leukemia (CLL); however, resistance may develop over time. Other lymphoid malignancies such as diffuse large B cell lymphoma (DLBCL) are frequently intrinsically resistant to venetoclax. Although genomic resistance mechanisms such as BCL2 mutations have been described, this probably only explains a subset of resistant cases. Using 2 complementary functional precision medicine techniques — BH3 profiling and high-throughput kinase activity mapping — we found that hyperphosphorylation of BCL-2 family proteins, including antiapo...
Source: Journal of Clinical Investigation - November 15, 2023 Category: Biomedical Science Authors: Stephen Jun Fei Chong, Fen Zhu, Olga Dashevsky, Rin Mizuno, Jolin X.H. Lai, Liam Hackett, Christine E. Ryan, Mary C. Collins, J. Bryan Iorgulescu, Romain Guièze, Johany Penailillo, Ruben Carrasco, Yeonjoo C. Hwang, Denise P. Muñoz, Mehdi Bouhaddou, Yaw Source Type: research
Glucagon-like peptide-1 receptor blockade impairs islet secretion and glucose metabolism in humans
CONCLUSION These data show that GLP1R blockade impairs islet function, implying that intra-islet GLP1R activation alters islet responses to glucose and does so to a greater degree in people with type 2 diabetes.TRIAL REGISTRATION This study was registered at ClinicalTrials.gov NCT04466618.FUNDING The study was primarily funded by NIH NIDDK DK126206. AV is supported by DK78646, DK116231 and DK126206. CDM was supported by MIUR (Italian Minister for Education) under the initiative “Departments of Excellence” (Law 232/2016). (Source: Journal of Clinical Investigation)
Source: Journal of Clinical Investigation - November 15, 2023 Category: Biomedical Science Authors: Andrew A. Welch, Rahele A. Farahani, Aoife M. Egan, Marcello C. Laurenti, Maya Zeini, Max Vella, Kent R. Bailey, Claudio Cobelli, Chiara Dalla Man, Aleksey Matveyenko, Adrian Vella Source Type: research
Recent advances in lung organoid development and applications in disease modeling
Over the last decade, several organoid models have evolved to acquire increasing cellular, structural, and functional complexity. Advanced lung organoid platforms derived from various sources, including adult, fetal, and induced pluripotent stem cells, have now been generated, which more closely mimic the cellular architecture found within the airways and alveoli. In this regard, the establishment of novel protocols with optimized stem cell isolation and culture conditions has given rise to an array of models able to study key cellular and molecular players involved in lung injury and repair. In addition, introduction of o...
Source: Journal of Clinical Investigation - November 15, 2023 Category: Biomedical Science Authors: Ana I. Vazquez-Armendariz, Purushothama Rao Tata Source Type: research
A cyclic pyrrole-imidazole polyamide reduces pathogenic RNA in CAG/CTG triplet repeat neurological disease models
Expansion of CAG and CTG (CWG) triplet repeats causes several inherited neurological diseases. The CWG repeat diseases are thought to involve complex pathogenic mechanisms through expanded CWG repeat–derived RNAs in a noncoding region and polypeptides in a coding region, respectively. However, an effective therapeutic approach has not been established for the CWG repeat diseases. Here, we show that a CWG repeat DNA–targeting compound, cyclic pyrrole–imidazole polyamide (CWG-cPIP), suppressed the pathogenesis of coding and noncoding CWG repeat diseases. CWG-cPIP bound to the hairpin form of mismatched CWG DNA, interfe...
Source: Journal of Clinical Investigation - November 15, 2023 Category: Biomedical Science Authors: Susumu Ikenoshita, Kazuya Matsuo, Yasushi Yabuki, Kosuke Kawakubo, Sefan Asamitsu, Karin Hori, Shingo Usuki, Yuki Hirose, Toshikazu Bando, Kimi Araki, Mitsuharu Ueda, Hiroshi Sugiyama, Norifumi Shioda Source Type: research
“Stuck in the Middle with You”: intermediate cell states are not always in transition
The era of single-cell multiomics has led to the identification of lung epithelial cells with features of both alveolar type 1 (AT1) and alveolar type 2 (AT2) pneumocytes, leading many to infer that these cells are a distinct cell type in the process of transitioning between AT2 and AT1 cells. In this issue of the JCI, Wang and colleagues demonstrated that many so-called “transitional cells” do not actually contribute to functional repair. The findings warrant a reimagining of these cells as existing in a nondirectional, intermediate cell state, rather than moving through a transitory process from one cell type to anot...
Source: Journal of Clinical Investigation - November 15, 2023 Category: Biomedical Science Authors: Jennifer M.S. Sucre, A. Scott McCall, Jonathan A. Kropski Source Type: research
Regulation of epithelial transitional states in murine and human pulmonary fibrosis
Idiopathic pulmonary fibrosis (IPF) is a progressive scarring disease arising from impaired regeneration of the alveolar epithelium after injury. During regeneration, type 2 alveolar epithelial cells (AEC2s) assume a transitional state that upregulates multiple keratins and ultimately differentiate into AEC1s. In IPF, transitional AECs accumulate with ineffectual AEC1 differentiation. However, whether and how transitional cells cause fibrosis, whether keratins regulate transitional cell accumulation and fibrosis, and why transitional AECs and fibrosis resolve in mouse models but accumulate in IPF are unclear. Here, we show...
Source: Journal of Clinical Investigation - November 15, 2023 Category: Biomedical Science Authors: Fa Wang, Christopher Ting, Kent A. Riemondy, Michael Douglas, Kendall Foster, Nisha Patel, Norihito Kaku, Alexander Linsalata, Jean Nemzek, Brian M. Varisco, Erez Cohen, Jasmine A. Wilson, David W.H. Riches, Elizabeth F. Redente, Diana M. Toivola, Xiaofen Source Type: research
Intratumoral androgen biosynthesis associated with 3β-hydroxysteroid dehydrogenase 1 promotes resistance to radiotherapy in prostate cancer
In conclusion, 3βHSD1 promotes prostate cancer resistance to combined androgen deprivation and radiotherapy by upregulating DNA DSB repair. This work supports prospective validation of early combined androgen blockade for high-risk men harboring the HSD3B1 (1245C) allele. (Source: Journal of Clinical Investigation)
Source: Journal of Clinical Investigation - November 15, 2023 Category: Biomedical Science Authors: Shinjini Ganguly, Zaeem Lone, Andrew Muskara, Jarrell Imamura, Aimalie Hardaway, Mona Patel, Mike Berk, Timothy D. Smile, Elai Davicioni, Kevin L. Stephans, Jay Ciezki, Christopher J. Weight, Shilpa Gupta, Chandana A. Reddy, Rahul D. Tendulkar, Abhishek A Source Type: research
The catalytic subunit of DNA-PK regulates transcription and splicing of AR in advanced prostate cancer
Aberrant androgen receptor (AR) signaling drives prostate cancer (PC), and it is a key therapeutic target. Although initially effective, the generation of alternatively spliced AR variants (AR-Vs) compromises efficacy of treatments. In contrast to full-length AR (AR-FL), AR-Vs constitutively activate androgenic signaling and are refractory to the current repertoire of AR-targeting therapies, which together drive disease progression. There is an unmet clinical need, therefore, to develop more durable PC therapies that can attenuate AR-V function. Exploiting the requirement of coregulatory proteins for AR-V function has the ...
Source: Journal of Clinical Investigation - November 15, 2023 Category: Biomedical Science Authors: Beth Adamson, Nicholas Brittain, Laura Walker, Ruaridh Duncan, Sara Luzzi, Pasquale Rescigno, Graham Smith, Suzanne McGill, Richard J.S. Burchmore, Elaine Willmore, Ian Hickson, Craig N. Robson, Denisa Bogdan, Juan M. Jimenez-Vacas, Alec Paschalis, Jonath Source Type: research
LAIR-1 agonism as a therapy for acute myeloid leukemia
Effective eradication of leukemic stem cells (LSCs) remains the greatest challenge in treating acute myeloid leukemia (AML). The immune receptor LAIR-1 has been shown to regulate LSC survival; however, the therapeutic potential of this pathway remains unexplored. We developed a therapeutic LAIR-1 agonist antibody, NC525, that induced cell death of LSCs, but not healthy hematopoietic stem cells in vitro, and killed LSCs and AML blasts in both cell- and patient-derived xenograft models. We showed that LAIR-1 agonism drives a unique apoptotic signaling program in leukemic cells that was enhanced in the presence of collagen. N...
Source: Journal of Clinical Investigation - November 15, 2023 Category: Biomedical Science Authors: Rustin R. Lovewell, Junshik Hong, Subhadip Kundu, Carly M. Fielder, Qianni Hu, Kwang Woon Kim, Haley E. Ramsey, Agnieszka E. Gorska, Londa S. Fuller, Linjie Tian, Priyanka Kothari, Ana Paucarmayta, Emily F. Mason, Ingrid Meza, Yanira Manzanarez, Jason Bos Source Type: research
Population-level single-cell genomics reveals conserved gene programs in systemic juvenile idiopathic arthritis
Systemic autoimmune and autoinflammatory diseases are characterized by genetic and cellular heterogeneity. While current single-cell genomics methods provide insights into known disease subtypes, these analysis methods do not readily reveal novel cell-type perturbation programs shared among distinct patient subsets. Here, we performed single-cell RNA-Seq of PBMCs of patients with systemic juvenile idiopathic arthritis (SJIA) with diverse clinical manifestations, including macrophage activation syndrome (MAS) and lung disease (LD). We introduced two new computational frameworks called UDON and SATAY-UDON, which define patie...
Source: Journal of Clinical Investigation - November 15, 2023 Category: Biomedical Science Authors: Emely L. Verweyen, Kairavee Thakkar, Sanjeev Dhakal, Elizabeth Baker, Kashish Chetal, Daniel Schnell, Scott Canna, Alexei A. Grom, Nathan Salomonis, Grant S. Schulert Source Type: research
Dietary branched-chain amino acids get to the heart of H3K23Pr
Cardiac metabolism provides effects that extend beyond the transformation of energy for the heart to operate effectively. Some metabolites also function as signaling molecules and exert transcriptional changes. Heart failure is a progressive pathology in which these metabolite functions falter. In this issue of the JCI, Yang et al. describe a protective effect from a low–branched chain amino acid (BCAA) diet in a mouse model of heart failure. The findings implicate a propionylation mark on histone H3 lysine 23 (H3K23Pr), previously shown to be dependent on the BCAA isoleucine, in transcriptional control of the cardiac st...
Source: Journal of Clinical Investigation - November 15, 2023 Category: Biomedical Science Authors: Christina Demetriadou, Daniel S. Kantner, Nathaniel W. Snyder Source Type: research
