Pharmacologic LDH inhibition redirects intratumoral glucose uptake and improves antitumor immunity in solid tumor models.

Tumor reliance on glycolysis is a hallmark of cancer. Immunotherapy is more effective in controlling glycolysis-low tumors lacking lactate dehydrogenase (LDH) due to reduced tumor lactate efflux and enhanced glucose availability within the tumor microenvironment (TME). LDH inhibitors (LDHi) reduce glucose uptake and tumor growth in preclinical models, but their impact on tumor-infiltrating T cells is not fully elucidated. Tumor cells have higher basal LDH expression and glycolysis levels compared with infiltrating T cells, creating a therapeutic opportunity for tumor-specific targeting of glycolysis. We demonstrate that LDHi treatment (a) decreases tumor cell glucose uptake, expression of the glucose transporter GLUT1, and tumor cell proliferation while (b) increasing glucose uptake, GLUT1 expression, and proliferation of tumor-infiltrating T cells. Accordingly, increasing glucose availability in the microenvironment via LDH inhibition leads to improved tumor-killing T cell function and impaired Treg immunosuppressive activity in vitro. Moreover, combining LDH inhibition with immune checkpoint blockade therapy effectively controls murine melanoma and colon cancer progression by promoting effector T cell infiltration and activation while destabilizing Tregs. Our results establish LDH inhibition as an effective strategy for rebalancing glucose availability for T cells within the TME, which can enhance T cell function and antitumor immunity.

The Role of Bone Grafting vs. Bone Cement in the Treatment of Giant Cell Tumor of Bone: A Systematic Review and Meta-Analysis on the Risk of Recurrence in 1,454 Patients.

BACKGROUND: Giant cell tumor of bone (GCTB) presents a challenge in management due to its invasive nature and propensity for local recurrence. While either bone grafting (BG) or bone cement (BC) can be utilized to fill defects after intralesional curettage, the optimal treatment remains contested. The purpose of this study was to examine the impact of defect filling with BC compared with BG on recurrence rates in patients with GCTB following intralesional curettage. METHODS: A random-effects model binary outcome meta-analysis was performed utilizing recurrence rate for the BC and BG groups to evaluate the risk ratio (p < 0.05 considered significant). There were 1,454 patients included. RESULTS: Intralesional curettage with BG had a recurrence risk ratio of 1.68 (95% confidence interval [CI], 1.22-2.31, p = 0.001) when compared with BC. The overall rate of recurrence for GCTB after intralesional curettage with BC was 20.05% vs. 29.74% with BG (95% CI, 0.17-0.23 vs. 0.26-0.33, p < 0.001). CONCLUSION: Intralesional curettage with BC for the treatment of GCTB demonstrated lower recurrence rates than intralesional curettage with BG. However, the rates of recurrence remain substantial for both groups, necessitating careful consideration of the benefits and potential pitfalls associated with BC vs. BG when considering salvage options after recurrences. LEVEL OF EVIDENCE: Level III. See Instructions for Authors for a complete description of levels of evidence.

Regulated induced proximity targeting chimeras-RIPTACs-A heterobifunctional small molecule strategy for cancer selective therapies.

We describe a protein proximity inducing therapeutic modality called Regulated Induced Proximity Targeting Chimeras or RIPTACs: heterobifunctional small molecules that elicit a stable ternary complex between a target protein (TP) selectively expressed in tumor cells and a pan-expressed protein essential for cell survival. The resulting co-operative protein-protein interaction (PPI) abrogates the function of the essential protein, thus leading to death selectively in cells expressing the TP. This approach leverages differentially expressed intracellular proteins as novel cancer targets, with the advantage of not requiring the target to be a disease driver. In this chemical biology study, we design RIPTACs that incorporate a ligand against a model TP connected via a linker to effector ligands such as JQ1 (BRD4) or BI2536 (PLK1) or CDK inhibitors such as TMX3013 or dinaciclib. RIPTACs accumulate selectively in cells expressing the HaloTag-FKBP target, form co-operative intracellular ternary complexes, and induce an anti-proliferative response in target-expressing cells.

Intermittent MEK Inhibition with GITR Costimulation Rescues T-cell Function for Increased Efficacy with CTLA-4 Blockade in Solid Tumor Models.

MEK inhibitors (MEKi) have shown limited success as a treatment for MAPK/ERK pathway-dependent cancers due to various resistance mechanisms tumor cells can employ. CH5126766 (CKI27) is an inhibitor that binds to MEK and prevents release of RAF, reducing the relief of negative feedback commonly observed with other MEKis. We observed that CKI27 increased MHC expression in tumor cells and improved T cell-mediated killing. Yet, CKI27 also decreased T-cell proliferation, activation, and cytolytic activity by inhibiting the MAPK/ERK pathway that is activated downstream of T-cell receptor signaling. Therefore, we aimed to balance the positive and negative immunomodulatory effects of MEKis for optimal combination with immunotherapy. Intermittent administration of CKI27 allowed T cells to partially recover and costimulation via GITR and OX-40 agonist antibodies completely alleviated inhibition of function. In Kras mutant lung and colon tumor mouse models, intermittent CKI27 and anti-GITR significantly decreased tumor growth and prolonged survival when further combined with CTLA-4 immune checkpoint blockade. Moreover, this triple combination increased CD8+ and CD4+ T-cell proliferation, activation, and effector/memory subsets in the tumor-draining lymph nodes and tumors and led to intratumoral regulatory T-cell destabilization. These data, collectively, will allow for more informed decisions when optimizing combination regimens by overcoming resistance, reducing toxicity, and generating long-term immune responses.

Navigating the Incidence of Postoperative Arrhythmia and Hospitalization Length: The Role of Amiodarone and Other Antiarrhythmics in Prophylaxis.

Antiarrhythmic drugs play a pivotal role in managing and preventing arrhythmias. Amiodarone, classified as a class III antiarrhythmic, has been used prophylactically to effectively prevent atrial fibrillation postoperatively in cardiac surgeries. However, there is a lack of consensus on the use of amiodarone and other antiarrhythmic drugs as prophylaxis to reduce the occurrence of all types of postoperative arrhythmias in cardiac and non-cardiac surgeries. A comprehensive PubMed query yielded 614 relevant papers, of which 52 clinical trials were analyzed. The data collection included the class of antiarrhythmics, timing or method of drug administration, surgery type, type of arrhythmia and its incidence, and hospitalization length. Statistical analyses focused on prophylactic antiarrhythmics and their respective reductions in postoperative arrhythmias and hospitalization length. Prophylactic amiodarone alone compared to placebo demonstrated a significant reduction in postoperative arrhythmia incidence in cardiac and non-cardiac surgeries (24.01%, p<0.0001), and it was the only treatment group to significantly reduce hospitalization length versus placebo (p = 0.0441). Prophylactic use of class 4 antiarrhythmics versus placebo also demonstrated a significant reduction in postoperative arrhythmia incidence (28.01%, p<0.0001), and while there was no significant statistical reduction compared to amiodarone (4%, p=0.9941), a lack of abundant data provides a case for further research on the prophylactic use of class 4 antiarrhythmics for this indication. Amiodarone prophylaxis remains a prime cornerstone of therapy in reducing postoperative arrhythmia incidence and hospitalization length. Emerging data suggests a need for a broader exploration of alternative antiarrhythmic agents and combination therapies, particularly class 4 antiarrhythmics, in both cardiac and non-cardiac surgeries. This meta-analysis depicts the effectiveness of amiodarone, among other antiarrhythmics, in postoperative arrhythmia incidence and hospitalization length reduction in cardiac and non-cardiac surgeries.

Benzene Diffusion and Partitioning in Contaminated Drinking Water Pipes under Stagnant Conditions.

Benzene contamination in drinking water systems affected by wildfires is a problem of emerging concern. Polyethylene pipes used in service lines and premise plumbing are vulnerable to permeation by benzene and can potentially cause challenges in sampling and remediation of contaminated systems. However, the kinetics and equilibria of the uptake of benzene by and release of benzene from pipes of differing polyethylene types and manufacturers are not well studied, leading to additional uncertainty when interpreting sampling data and selecting remediation options. This work addresses this data gap by providing diffusion and partitioning data for benzene and several varieties of polyethylene pipes, including field samples from water distribution systems. All polyethylene pipes that were studied exhibited similar partitioning behavior during benzene uptake and release, but some differences in kinetics were observed among pipes. However, these differences were of minor practical importance in the pipe contamination scenario examined in this work. The results of this study can be used in conjunction with diffusion modeling to inform remediation decisions for benzene-contaminated, polyethylene service lines, and premise plumbing.

Exploring the Role of External Beam Radiation Therapy in Osteosarcoma Treatment: Impact of Diagnostic Imaging Delays and Innovative Techniques.

Osteosarcomas are a type of bone cancer that typically affect young adults, often in the bones of the arms and legs. To treat osteosarcoma, doctors typically use a combination of chemotherapy, radiotherapy, and surgery, with External Beam Radiation Therapy (EBRT) being the most commonly used form of radiotherapy. EBRT involves directing high-energy photons, X-rays, gamma rays, protons, and electrons at the tumor to induce cancer cell death. Additionally, healthcare providers use imaging techniques to monitor treatment success. This literature review aims to explore the relationship between osteosarcomas and EBRT, investigate the impact of the delayed diagnosis on survival rates, and examine the effectiveness of innovative uses of EBRT for treating osteosarcomas in unusual locations using comprehensive diagnostic techniques. To achieve these objectives, the review examines case studies and literary analyses and categorizes them based on the delay between symptom onset and diagnosis. The null hypothesis is that the presence or absence of a delay in diagnosis does not significantly impact outcomes for the "Delay" category. A lack of delay results in a more favorable outcome in the "Lack of Delay" category. However, the data and statistical results suggest that additional follow-up care in patients with rare or commonly recurring cancers could benefit outcomes. It is important to note that due to the rarity of osteosarcoma with EBRT, the small sample size in the studies warrants further investigation. Interestingly, many patients presented with head and neck tumors despite the most common location of osteosarcoma being in the long bones.

Nickel-Catalyzed Isomerization of Homoallylic Alcohols.

Nickel-catalyzed isomerizations of homoallylic alcohols and a bishomoallylic alcohol are presented. These isomerization reactions occur in the presence of a simple nickel catalyst that does not require addition of an exogenous ligand. The corresponding ketone products are generated in ≤98% yield.

Regulated Induced Proximity Targeting Chimeras (RIPTACs): a Novel Heterobifunctional Small Molecule Therapeutic Strategy for Killing Cancer Cells Selectively.

While specific cell signaling pathway inhibitors have yielded great success in oncology, directly triggering cancer cell death is one of the great drug discovery challenges facing biomedical research in the era of precision oncology. Attempts to eradicate cancer cells expressing unique target proteins, such as antibody-drug conjugates (ADCs), T-cell engaging therapies, and radiopharmaceuticals have been successful in the clinic, but they are limited by the number of targets given the inability to target intracellular proteins. More recently, heterobifunctional small molecules such as Proteolysis Targeting Chimera (PROTACs) have paved the way for protein proximity inducing therapeutic modalities. Here, we describe a proof-of-concept study using novel heterobifunctional small molecules called Regulated Induced Proximity Targeting Chimeras or RIPTACs, which elicit a stable ternary complex between a target protein selectively expressed in cancer tissue and a pan-expressed protein essential for cell survival. The resulting cooperative protein:protein interaction (PPI) abrogates the function of the essential protein, thus leading to cell death selectively in cells expressing the target protein. This approach not only opens new target space by leveraging differentially expressed intracellular proteins but also has the advantage of not requiring the target to be a driver of disease. Thus, RIPTACs can address non-target mechanisms of resistance given that cell killing is driven by inactivation of the essential protein. Using the HaloTag7-FKBP model system as a target protein, we describe RIPTACs that incorporate a covalent or non-covalent target ligand connected via a linker to effector ligands such as JQ1 (BRD4), BI2536 (PLK1), or multi-CDK inhibitors such as TMX3013 or dinaciclib. We show that these RIPTACs exhibit positive co-operativity, accumulate selectively in cells expressing HaloTag7-FKBP, form stable target:RIPTAC:effector trimers in cells, and induce an anti-proliferative response in target-expressing cells. We propose that RIPTACs are a novel heterobifunctional therapeutic modality to treat cancers that are known to selectively express a specific intracellular protein.

Emotional, hyperactivity and inattention problems in adolescents with immunocompromising chronic diseases during the COVID-19 pandemic

Abstract Objective: To assess factors associated with emotional changes and Hyperactivity/Inattention (HI) motivated by COVID-19 quarantine in adolescents with immunocompromising diseases. Methods: A cross-sectional study included 343 adolescents with immunocompromising diseases and 108 healthy adolescents. Online questionnaires were answered including socio-demographic data and self-rated healthcare routine during COVID-19 quarantine and validated surveys: Strengths and Difficulties Questionnaire (SDQ), Pittsburgh Sleep Quality Index (PSQI), Pediatric Quality of Life Inventory 4.0 (PedsQL4.0). Results: The frequencies of abnormal emotional SDQ scores from adolescents with chronic diseases were similar to those of healthy subjects (110/343 [32%] vs. 38/108 [35%], p = 0.548), as well as abnormal hyperactivity/inattention SDQ scores (79/343 [23%] vs. 29/108 [27%], p = 0.417). Logistic regression analysis of independent variables associated with abnormal emotional scores from adolescents with chronic diseases showed: female sex (Odds Ratio [OR = 3.76]; 95% Confidence Interval (95% CI) 2.00-7.05; p < 0.001), poor sleep quality (OR = 2.05; 95% CI 1.08-3.88; p = 0.028) and intrafamilial violence during pandemic (OR = 2.17; 95% CI 1.12-4.19; p = 0.021) as independently associated with abnormal emotional scores, whereas total PedsQL score was inversely associated with abnormal emotional scores (OR = 0.95; 95% CI 0.93-0.96; p < 0.0001). Logistic regression analysis associated with abnormal HI scores from patients evidenced that total PedsQL score (OR = 0.97; 95% CI 0.95-0.99; p = 0.010], changes in medical appointments during the pandemic (OR = 0.39; 95% CI 0.19-0.79; p = 0.021), and reliable COVID-19 information (OR = 0.35; 95% CI 0.16-0.77; p = 0.026) remained inversely associated with abnormal HI scores. Conclusion: The present study showed emotional and HI disturbances in adolescents with chronic immunosuppressive diseases during the COVID-19 pandemic. It reinforces the need to promptly implement a longitudinal program to protect the mental health of adolescents with and without chronic illnesses during future pandemics.

Nickel-Catalyzed Formation of α-Substituted γ-Amino Ketones via Alkene Carboacylation.

Herein, we report Ni-catalyzed intramolecular carboacylation of imides containing a tethered alkene and tetraarylborate nucleophiles. Using a nickel-phosphine catalyst system, α-substituted, γ-amino ketones are generated in up to 92% yield with site selectivity. Deprotection and cyclization of the γ-amino ketone product afforded a cyclic imine in 71% yield, and a stereoselective reduction formed the ß-substituted, δ-amino alcohol in 66% yield with 2.3:1 d.r. and 94% ee (major diastereomer).

Nickel-catalyzed arylative substitution of homoallylic alcohols.

Direct coupling of unactivated alcohols remains a challenge in synthetic chemistry. Current approaches to cross-coupling of alcohol-derived electrophiles often involve activated alcohols such as tosylates or carbonates. We report the direct arylative substitution of homoallylic alcohols catalyzed by a nickel-bisphosphine complex as a facile method to generate allylic arenes. These reactions proceed via formation of an allylic alcohol intermediate. Subsequent allylic substitution with arylboroxine nucleophiles enables the formation of a variety of allylic arenes. The presence of p-methoxyphenylboronic acid is crucial to activate the allylic alcohol to achieve high product yields.

AGA Clinical Practice Guideline on Pharmacological Interventions for Adults With Obesity.

BACKGROUND & AIMS: Pharmacological management of obesity improves outcomes and decreases the risk of obesity-related complications. This American Gastroenterological Association guideline is intended to support practitioners in decisions about pharmacological interventions for overweight and obesity. METHODS: A multidisciplinary panel of content experts and guideline methodologists used the Grading of Recommendations Assessment, Development and Evaluation framework to prioritize clinical questions, identify patient-centered outcomes, and conduct an evidence synthesis of the following agents: semaglutide 2.4 mg, liraglutide 3.0 mg, phentermine-topiramate extended-release (ER), naltrexone-bupropion ER, orlistat, phentermine, diethylpropion, and Gelesis100 oral superabsorbent hydrogel. The guideline panel used the evidence-to-decision framework to develop recommendations for the pharmacological management of obesity and provided implementation considerations for clinical practice. RESULTS: The guideline panel made 9 recommendations. The panel strongly recommended the use of pharmacotherapy in addition to lifestyle intervention in adults with overweight and obesity (body mass index ≥30 kg/m2, or ≥27 kg/m2 with weight-related complications) who have an inadequate response to lifestyle interventions. The panel suggested the use of semaglutide 2.4 mg, liraglutide 3.0 mg, phentermine-topiramate ER, and naltrexone-bupropion ER (based on moderate certainty evidence), and phentermine and diethylpropion (based on low certainty evidence), for long-term management of overweight and obesity. The guideline panel suggested against the use of orlistat. The panel identified the use of Gelesis100 oral superabsorbent hydrogel as a knowledge gap. CONCLUSIONS: In adults with overweight and obesity who have an inadequate response to lifestyle interventions alone, long-term pharmacological therapy is recommended, with multiple effective and safe treatment options.

Synthesis of oxaboranes via nickel-catalyzed dearylative cyclocondensation.

We report Ni-catalyzed dearylative cyclocondensation of aldehydes, alkynes, and triphenylborane. The reaction is initiated by oxidative cyclization of the aldehyde and alkyne coupling partners to generate an oxanickelacyclopentene which reacts with triphenylborane to form oxaboranes. This formal dearylative cyclocondensation reaction generates oxaboranes in moderate-to-high yields (47-99%) with high regioselectivities under mild reaction conditions. This approach represents a direct and modular synthesis of oxaboranes which are difficult to access using current methods. These oxaboranes are readily transformed into valuable building blocks for organic synthesis and an additional class of boron heterocycles. Selective homocoupling forms oxaboroles, oxidation generates aldol products, and reduction and arylation form substituted allylic alcohols.

Calreticulin mutant myeloproliferative neoplasms induce MHC-I skewing, which can be overcome by an optimized peptide cancer vaccine.

The majority of JAK2V617F-negative myeloproliferative neoplasms (MPNs) have disease-initiating frameshift mutations in calreticulin (CALR), resulting in a common carboxyl-terminal mutant fragment (CALRMUT), representing an attractive source of neoantigens for cancer vaccines. However, studies have shown that CALRMUT-specific T cells are rare in patients with CALRMUT MPN for unknown reasons. We examined class I major histocompatibility complex (MHC-I) allele frequencies in patients with CALRMUT MPN from two independent cohorts. We observed that MHC-I alleles that present CALRMUT neoepitopes with high affinity are underrepresented in patients with CALRMUT MPN. We speculated that this was due to an increased chance of immune-mediated tumor rejection by individuals expressing one of these MHC-I alleles such that the disease never clinically manifested. As a consequence of this MHC-I allele restriction, we reasoned that patients with CALRMUT MPN would not efficiently respond to a CALRMUT fragment cancer vaccine but would when immunized with a modified CALRMUT heteroclitic peptide vaccine approach. We found that heteroclitic CALRMUT peptides specifically designed for the MHC-I alleles of patients with CALRMUT MPN efficiently elicited a CALRMUT cross-reactive CD8+ T cell response in human peripheral blood samples but not to the matched weakly immunogenic CALRMUT native peptides. We corroborated this effect in vivo in mice and observed that C57BL/6J mice can mount a CD8+ T cell response to the CALRMUT fragment upon immunization with a CALRMUT heteroclitic, but not native, peptide. Together, our data emphasize the therapeutic potential of heteroclitic peptide-based cancer vaccines in patients with CALRMUT MPN.

Nickel-Catalyzed Enantioselective Hydroboration of Vinylarenes.

The enantioselective hydroboration of vinylarenes catalyzed by a chiral, nonracemic nickel catalyst is presented as a facile method for generating chiral benzylic boronate esters. Various vinylarenes react with bis(pinacolato)diboron (B2pin2) in the presence of MeOH as a hydride source to form chiral boronate esters in up to 92% yield with up to 94% ee. The use of anhydrous Me4NF to activate B2pin2 is crucial for ensuring fast transmetalation to achieve high enantioselectivities.

Vitamin D and COVID-19: A review on the role of vitamin D in preventing and reducing the severity of COVID-19 infection.

Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2) is a pathogenic coronavirus causing COVID-19 infection. The interaction between the SARS-CoV-2 spike protein and the human receptor angiotensin-converting enzyme 2, both of which contain several cysteine residues, is impacted by the disulfide-thiol balance in the host cell. The host cell redox status is affected by oxidative stress due to the imbalance between the reactive oxygen/nitrogen species and antioxidants. Recent studies have shown that Vitamin D supplementation could reduce oxidative stress. It has also been proposed that vitamin D at physiological concentration has preventive effects on many viral infections, including COVID-19. However, the molecular-level picture of the interplay of vitamin D deficiency, oxidative stress, and the severity of COVID-19 has remained unclear. Herein, we present a thorough review focusing on the possible molecular mechanism by which vitamin D could alter host cell redox status and block viral entry, thereby preventing COVID-19 infection or reducing the severity of the disease.

Nickel-Catalyzed Asymmetric Hydroarylation of Vinylarenes: Direct Enantioselective Synthesis of Chiral 1,1-Diarylethanes.

The enantioselective hydroarylation of vinylarenes catalyzed by a chiral, non-racemic nickel catalyst is presented as a facile method to generate chiral 1,1-diarylethanes. These reactions proceed via formation of a chiral, non-racemic nickel benzyl intermediate. Transmetalation with arylboron nucleophiles and subsequent reductive elimination enable the formation of a variety of chiral 1,1-diarylethanes. The 1,1-diarylethane products from reactions of arylboronic acids containing electron-donating substituents are formed with typically greater than 90% ee, while the 1,1-diarylethanes generated from reactions of arylboronic acids containing electron-withdrawing groups are generated with typically less than 80% ee. These results are consistent with the rate of transmetalation with an arylboron nucleophile playing a key role in the enantioselectivity of these hydroarylation reactions. This mechanistic insight has led to the development of reactions of neo-pentylglycolate esters of arylboronic acids with vinylarenes that occur with higher enantioselectivities based on increased rates of transmetalation.

Informing remediation of benzene contamination in drinking water distribution systems through multi-criteria decision analysis.

When contamination incidents occur in drinking water distribution systems, utilities need to select the remediation technologies most suited to their system-specific conditions and the contaminants of concern. Technology selection often involves balancing competing priorities. Multi-Criteria Decision Analysis (MCDA) is a promising approach that has been used extensively in other industries but not yet in drinking water system remediation. This paper discusses development of a computer-based tool that allows practitioners to leverage the Analytical Hierarchy Process (AHP), a well-established method of MCDA, to select remediation technologies based on their effectiveness and their compatibility with the practitioner's project objectives. This paper focuses on benzene, a contaminant implicated for many years in contamination incidents following spills and, more recently, wildfires.

Methane emissions from natural gas vehicles in China.

Natural gas vehicles (NGVs) have been promoted in China to mitigate air pollution, yet our measurements and analyses show that NGV growth in China may have significant negative impacts on climate change. We conducted real-world vehicle emission measurements in China and found high methane emissions from heavy-duty NGVs (90% higher than current emission limits). These emissions have been ignored in previous emission estimates, leading to biased results. Applying our observations to life-cycle analyses, we found that switching to NGVs from conventional vehicles in China has led to a net increase in greenhouse gas (GHG) emissions since 2000. With scenario analyses, we also show that the next decade will be critical for China to reverse the trend with the upcoming China VI standard for heavy-duty vehicles. Implementing and enforcing the China VI standard is challenging, and the method demonstrated here can provide critical information regarding the fleet-level CH4 emissions from NGVs.