NADH-bound AIF activates the mitochondrial CHCHD4/MIA40 chaperone by a substrate-mimicry mechanism.

Mitochondrial metabolism requires the chaperoned import of disulfide-stabilized proteins via CHCHD4/MIA40 and its enigmatic interaction with oxidoreductase Apoptosis-inducing factor (AIF). By crystallizing human CHCHD4's AIF-interaction domain with an activated AIF dimer, we uncover how NADH allosterically configures AIF to anchor CHCHD4's β-hairpin and histidine-helix motifs to the inner mitochondrial membrane. The structure further reveals a similarity between the AIF-interaction domain and recognition sequences of CHCHD4 substrates.

Prevention and Management of Posterior Wound Complications Following Oncologic Spine Surgery: Narrative Review of Available Evidence and Proposed Clinical Decision-Making Algorithm.

Study Design: Narrative Review.

Objective: Contextualized by a narrative review of recent literature, we propose a wound complication prevention and management algorithm for spinal oncology patients. We highlight available strategies and motivate future research to identify optimal and individualized wound management for this population.

Phase 1 Trial of TTI-101, a First-in-Class Oral Inhibitor of STAT3 in Patients with Advanced Solid Tumors.

Purpose: Signal transducer and activator of transcription 3 (STAT3) is a transcription factor that is essential for the survival and immune sequestration of cancer cells. We conducted a phase 1 study of TTI‑101, a first-in-class, selective small-molecule inhibitor of STAT3, in patients with advanced metastatic cancer.

Patients And Methods: Patients were treated with TTI-101 orally twice daily in 28-day cycles at 4 dose levels (DLs): 3.

DNTT-mediated DNA Damage Response Drives Inotuzumab Ozogamicin Resistance in B-cell Acute Lymphoblastic Leukemia.

Inotuzumab Ozogamicin (InO) is an antibody-calicheamicin conjugate with striking efficacy in B-cell acute lymphoblastic leukemia (B-ALL). However, there is wide inter-patient variability in treatment response, and the genetic basis of this variation remains largely unknown. Using a genome-wide CRISPR screen, we discovered the loss of DNTT as a primary driver of InO resistance.

High-Risk MCL: Recognition and Treatment.

Significant progress in determining the molecular origins and resistance mechanisms of mantle cell lymphoma (MCL) has improved our understanding of the disease's clinical diversity. These factors greatly impact prognosis in MCL patients. Given the dynamic alterations in MCL clones and disease evolution, it is crucial to recognize high-risk prognostic factors at diagnosis and relapse.

Outcomes of Older Adults and Frail Patients Receiving Idecabtagene Vicleucel: A CIBMTR Study.

Idecabtagene vicleucel (ide-cel) is an anti-BCMA CAR-T cell therapy approved for patients with relapsed/refractory multiple myeloma (RRMM) after 2 prior lines of therapy. There is limited data on outcomes of CAR T in older adults and frail patients with RRMM. In this study, we utilized data from the Center for International Blood and Marrow Transplantation Registry to describe the safety and efficacy of ide-cel in these clinically important subgroups.

Conventional Cytogenetic Analysis of Solid Tumor Abnormalities: A 25-Year Review of Proficiency Test Results from the College of American Pathologists/American College of Medical Genetics and Genomics Cytogenetics Committee.

The joint College of American Pathologists/American College of Medical Genetics and Genomics Cytogenetics Committee works to ensure the competency and proficiency of clinical cytogenetic testing laboratories through proficiency testing (PT) programs for various clinical tests offered by such laboratories, including the evaluation of cytogenetic abnormalities in solid tumors. Review and analyze 25 years (1999-2023) of solid tumor chromosome analysis PT results, utilizing G-banded karyograms. A retrospective review of results from 1999 to 2023 was performed, identifying the challenges addressing solid tumors.

Statins inhibit onco-dimerization of the 4Ig isoform of B7-H3.

B7-H3 (CD276), a member of the B7-family of immune checkpoint proteins, has been shown to have immunological and non-immunological effects promoting tumorigenesis [1, 2] and expression correlates with poor prognosis for many solid tumors, including cervical, ovarian and breast cancers [3-6]. We recently identified a tumor-cell autochthonous tumorigenic role for dimerization of the 4Ig isoform of B7-H3 (4Ig-B7-H3) [7], where 4Ig-B7-H3 dimerization activated tumor-intrinsic cellular proliferation and tumorigenesis pathways, providing a novel opportunity for therapeutic intervention. Herein, a live cell split-luciferase complementation strategy was used to visualize 4Ig-B7-H3 homodimerization in a high-throughput small molecule screen (HTS) to identify modulators of this protein-protein interaction (PPI).

Risk factors for local recurrence in patients with clinical stage II/III low rectal cancer: A multicenter retrospective cohort study in Japan.

Background: Identifying risk factors for local recurrence (LR) is pivotal in optimizing rectal cancer treatment. Total mesorectal excision (TME) and lateral lymph node dissection (LLND) are the standard treatment for advanced low rectal cancer in Japan. However, large-scale studies to evaluate risk factors for LR are limited.

SOX2-induced IL1α-mediated immune suppression drives epithelial dysplasia malignant transformation.

Squamous cell carcinomas (SCC) are often preceded by potentially malignant precursor lesions, most of which remain benign. The terminal exhaustion phenotypes of effector T-cells and the accumulation of myeloid-derived suppressor cells (MDSC) have been thoroughly characterized in established SCC. However, it is unclear what precancerous lesions harbor a bona fide high risk for malignant transformation and how precancerous epithelial dysplasia drives the immune system to the point of no return.

Olaparib and Radiotherapy Induce Type I Interferon- and CD8+ T Cell-Dependent Sensitization to Immunotherapy in Pancreatic Cancer.

PARP inhibitors sensitize pancreatic ductal adenocarcinoma (PDAC) to radiation by inducing DNA damage and replication stress. These mechanisms also have the potential to enhance radiation-induced type I interferon (T1IFN)-mediated antitumoral immune responses. We hypothesized that the PARP inhibitor olaparib would also potentiate radiation-induced T1IFN to promote antitumor immune responses and sensitization of otherwise resistant PDAC to immunotherapy.

Development of a RIPK1 degrader to enhance antitumor immunity.

The scaffolding function of receptor interacting protein kinase 1 (RIPK1) confers intrinsic and extrinsic resistance to immune checkpoint blockades (ICBs) and emerges as a promising target for improving cancer immunotherapies. To address the challenge posed by a poorly defined binding pocket within the intermediate domain of RIPK1, here we harness proteolysis targeting chimera (PROTAC) technology to develop a RIPK1 degrader, LD4172. LD4172 exhibits potent and selective RIPK1 degradation both in vitro and in vivo.

Systematic Review of the Comparative Studies of Image-guided Thermal Ablation, Stereotactic Radiosurgery, and Sublobar Resection for Treatment of High-Risk Patients with Stage I Non-Small Cell Lung Cancer.

The Clinical Practice Standards Committee of the American Association for Thoracic Surgery assembled an expert panel and conducted a systematic review of the literature detailing studies directly comparing treatment options for high-risk patients with stage I non-small cell lung cancer (NSCLC). A systematic search was performed to identify publications comparing outcomes following image-guided thermal ablation (IGTA), stereotactic ablative radiotherapy (SABR), and sublobar resection-the main treatment options applicable to high-risk patients with stage I NSCLC. There were no publications detailing completed randomized controlled trials comparing these treatment options.

Systematic Review of Stereotactic Ablative Radiotherapy (SABR)/ Stereotactic Body Radiation Therapy (SBRT) for Treatment of High-Risk Patients with Stage I Non-Small Cell Lung Cancer.

Stereotactic ablative radiotherapy (SABR) has emerged as an alternative, non-surgical treatment for high-risk patients with stage I non-small cell lung cancer (NSCLC) with increased use over time. The American Association for Thoracic Surgery (AATS) Clinical Practice Standards Committee (CPSC) assembled an expert panel and conducted a systematic review of the literature evaluating the results of SABR, which is also referred to as stereotactic body radiation therapy (SBRT) or stereotactic radiosurgery (SRS), prior to developing treatment recommendations for high-risk patients with stage I NSCLC based on expert consensus. Publications detailing the findings of 16 prospective studies of SABR and 14 retrospective studies of SABR for the management of early-stage lung cancer in 54 697 patients were identified by systematic review of the literature with further review by members of our expert panel.

Systematic Review of Sublobar Resection for Treatment of High-Risk Patients with Stage I Non-Small Cell Lung Cancer.

Sublobar resection offers a parenchymal-sparing surgical alternative to lobectomy and includes wedge resection and segmentectomy. Sublobar resection has been historically utilized in high-risk patients with compromised lung function; however, the technique is becoming more prevalent for normal-risk patients with peripheral lung tumors < 2 cm. In this article, we summarize the technique of sublobar resection, the importance of surgical margins and lymph node sampling, patient selection, perioperative complications, outcomes, and the impact of sublobar resection on the quality of life.

In vitro hydrolysis of areca nut xenobiotics in human liver.

Areca nut (AN) is a substance of abuse consumed by millions worldwide, in spite of established oral and systemic toxicities associated with its use. Previous research demonstrates methyl ester alkaloids in the AN, such as arecoline and guvacoline, exhibit mood-altering and toxicological effects. Nonetheless, their metabolism has not been fully elucidated in humans.

Treatment Selection for the High-risk Patient with Stage I Non-Small Cell Lung Cancer: Sublobar Resection, Stereotactic Ablative Radiotherapy or Image-guided Thermal Ablation?

Objective: A significant proportion of patients with stage I non-small cell lung cancer (NSCLC) are considered at high risk for complications or mortality after lobectomy. The American Association for Thoracic Surgery (AATS) previously published an expert consensus document detailing important considerations in determining who is at high risk. The current objective was to evaluate treatment options and important factors to consider during treatment selection for these high-risk patients.

Systematic Review of Image-guided Thermal Ablation for Treatment of High-Risk Patients with Stage I Non-Small Cell Lung Cancer.

Image-guided thermal ablation (IGTA) applied to pulmonary pathology is an alternative to surgery in high-risk patients with stage I non-small cell lung cancer (NSCLC). Its application to lung neoplasm was first introduced in 2001 and has been implemented to treat metastatic disease to the lung or in select medically inoperable patients with peripheral stage I NSCLC. IGTA may also be an alternative to treat stage I NSCLC in non-operable patients with interstitial lung disease in whom a radiation modality is deemed too high risk.

The Importance of Pulmonary Nodule Features in the Selection of Treatment for the High-risk Patient with Stage I Non-Small Cell Lung Cancer.

Objective: The American Association for Thoracic Surgery (AATS) Clinical Practice Standards Committee (CPSC) previously published important considerations in determining who is at high risk for complications or mortality after lobectomy. Sublobar resection, stereotactic ablative radiotherapy, or image-guided thermal ablation is typically considered when the risks associated with lobectomy are high. The current objective was to evaluate important lung-nodule-related factors to consider during treatment selection for high-risk patients with stage I non-small cell lung cancer (NSCLC).

Patient-reported outcomes after CAR T-cell therapy in patients with hematological malignancies.

The remarkable improvement in survival among individuals with hematological malignancies receiving chimeric antigen receptor (CAR) T-cell therapy has highlighted the growing unmet need to incorporate patient-centered assessments in management guidelines for these patients. That CAR T-cell therapy is associated with unique toxicities and relatively high symptom burden in the first few weeks after cell infusion is well known. Magnifying the patient's voice by using patient-reported outcomes (PROs) might support personalized intervention in the acute-care setting, optimize the use of medical resources, improve satisfaction with therapy, and enhance survival benefit.