Local Therapy Improves Survival for Early Recurrence After Resection of Colorectal Liver Metastases.

BACKGROUND: Early recurrence following hepatectomy for colorectal liver metastases (CLM) is associated with worse survival; yet, impact of further local therapy is unclear. We sought to evaluate whether local therapy benefits patients with early recurrence following hepatectomy for CLM. METHODS: Clinicopathologic and survival outcomes of patients managed with hepatectomy for CLM (1/2001-12/2020) were queried from a prospectively maintained database. Timing of recurrence was stratified as early (recurrence-free survival [RFS] < 6 months), intermediate (RFS 6-12 months), and later (RFS > 12 months). Local therapy was defined as ablation, resection, or radiation. RESULTS: Of 671 patients, 541 (81%) recurred with 189 (28%) early, 180 (27%) intermediate, and 172 (26%) later recurrences. Local therapy for recurrence resulted in improved survival, regardless of recurrence timing (early 78 vs. 32 months, intermediate 72 vs. 39 months, later 132 vs. 65 months, all p < 0.001). Following recurrence, treatment with local therapy (hazard ratio [HR] = 0.24), liver and extrahepatic recurrence (HR = 1.81), RAS + TP53 co-mutation (HR = 1.52), and SMAD4 mutation (HR = 1.92) were independently associated with overall survival (all p ≤ 0.002). Among patients with recurrence treated by local therapy, patients older than 65 years (HR 1.79), liver and extrahepatic recurrence (HR 2.05), primary site or other recurrence (HR 1.90), RAS-TP53 co-mutation (HR 1.63), and SMAD4 mutation (HR 2.06) had shorter post-local therapy survival (all p ≤ 0.04). CONCLUSIONS: While most patients recur after hepatectomy for CLM, local therapy may result in long-term survival despite early recurrence. Somatic mutational profiling may help to guide the multidisciplinary consideration of local therapy after recurrence.

Effects of Small Molecule Ligands on ACKR3 Receptors.

Chemokines such as stromal derived factor 1 and their G protein coupled receptors are well-known regulators of the development and functions of numerous tissues. C-X-C motif chemokine ligand 12 (CXCL12) has two receptors: C-X-C chemokine motif receptor 4 (CXCR4) and atypical chemokine receptor 3 (ACKR3). ACKR3 has been described as an atypical "biased" receptor because it does not appear to signal through G proteins and, instead, signals solely through the ß-arrestin pathway. In support of this conclusion, we have shown that ACKR3 is unable to signal through any of the known mammalian G α isoforms and have generated a comprehensive map of the G α activation by CXCL12/CXCR4. We also synthesized a series of small molecule ligands which acted as selective agonists for ACKR3 as assessed by their ability to recruit ß-arrestin to the receptor. Using select point mutations, we studied the molecular characteristics that determine the ability of small molecules to activate ACKR3 receptors, revealing a key role for the deeper binding pocket composed of residues in the transmembrane domains of ACKR3. The development of more selective ACKR3 ligands should allow us to better appreciate the unique roles of ACKR3 in the CXCL12/CXCR4/ACKR3-signaling axis and better understand the structural determinants for ACKR3 activation. SIGNIFICANCE STATEMENT: We are interested in the signaling produced by the G protein coupled receptor atypical chemokine receptor 3 (ACKR3), which signals atypically. In this study, novel selective ligands for ACKR3 were discovered and the site of interactions between these small molecules and ACKR3 was defined. This work will help to better understand the unique signaling roles of ACKR3.

Discovery of a novel class of potent and selective tetrahydroindazole-based sigma-1 receptor ligands.

The sigma-1 and sigma-2 receptors have been shown to play important roles in CNS diseases, cancer, and other disorders. These findings suggest that targeting these proteins with small-molecule modulators may be of important therapeutic value. Here we report the development of a new class of tetrahydroindazoles that are highly potent and selective ligands for sigma-1. Molecular modeling was used to rationalize the observed structure-activity relationships and identify key interactions responsible for increased potency of the optimized compounds. Assays for solubility and microsomal stability showed this series possesses favorable characteristics and is amenable to further therapeutic development. The compounds described herein will be useful in the development of new chemical probes for sigma-1 and to aid in future work therapeutically targeting this protein.

Synthesis of a novel fused pyrrolodiazepine-based library with anti-cancer activity.

Development of drugs for new and persistent diseases will increasingly rely on the expansion of accessible chemical space to allow exploration of novel molecular targets. Here we report the synthesis of a library of novel fused heterobicyclic small molecules based on the 1,4-diazepine and 2,4-pyrrolidinedione scaffolds. Key chemical transformations included a Mannich-type condensation and chemoselective N-acylation reactions. Screening shows anti-cancer activity of several library compounds which suggests translational potential of this novel chemical scaffold.

Cancer metabolism and the Warburg effect: the role of HIF-1 and PI3K.

Cancer cells have been shown to have altered metabolism when compared to normal non-malignant cells. The Warburg effect describes a phenomenon in which cancer cells preferentially metabolize glucose by glycolysis, producing lactate as an end product, despite being the presence of oxygen. The phenomenon was first described by Otto Warburg in the 1920s, and has resurfaced as a controversial theory, with both supportive and opposing arguments. The biochemical aspects of the Warburg effect outline a strong explanation for the cause of cancer cell proliferation, by providing the biological requirements for a cell to grow. Studies have shown that pathways such as phosphoinositide 3-kinase/protein kinase B/mammalian target of rapamycin (PI3K/Akt/mTOR) as well as hypoxia inducible factor-1 (HIF-1) are central regulators of glycolysis, cancer metabolism and cancer cell proliferation. Studies have shown that PI3K signaling pathways have a role in many cellular processes such as metabolism, inflammation, cell survival, motility and cancer progression. Herein, the cellular aspects of the PI3K pathway are described, as well as the influence HIF has on cancer cell metabolism. HIF-1 activation has been related to angiogenesis, erythropoiesis and modulation of key enzymes involved in aerobic glycolysis, thereby modulating key processes required for the Warburg effect. In this review we discuss the molecular aspects of the Warburg effect with a particular emphasis on the role of the HIF-1 and the PI3K pathway.

Total Synthesis of (±)-Glyceollin II and a Dihydro Derivative.

Stressed soybeans produce a group of phytoalexins that belong to the 6a-hydroxypterocarpan family of flavonoids. Certain of the more prominent members, such as the glyceollins I, II, and III, have demonstrated potential antidiabetic properties and promising cytotoxicity in both human breast and prostate cancer cell cultures with preliminary studies in animals further demonstrating antitumor effects in estrogen-dependent, human breast cancer cell implants. Although syntheses of glyceollin I have been reported previously, this work constitutes the first total directed synthesis of (±)-glyceollin II. It involves 12 steps with an overall yield of 7% using practical methods that should be readily scalable to produce quantities needed for advanced biological characterization. Highlights include a novel intramolecular benzoin condensation, a chelation-controlled lithium aluminum hydride-mediated reduction, and an intramolecular cyclization via the formation of a transient epoxide intermediate to cap the construction of the 6a-hydroxypterocarpan system. Additionally, a dihydro analogue has been obtained, and several isolated intermediates have been made available for evaluation of their biological properties and possible contributions toward elaborating key structure-activity relationship data among this family of promising phytoalexins elicited from stressed soybeans.

γH2AX in mouse embryonic stem cells: Distribution during differentiation and following γ-irradiation.

Phosphorylated histone H2AX (γH2AX) represents a sensitive molecular marker of DNA double-strand breaks (DSBs) and is implicated in stem cell biology. We established a model of mouse embryonic stem cell (mESC) differentiation and examined the dynamics of γH2AX foci during the process. Our results revealed high numbers of γH2AX foci in undifferentiated mESCs, decreasing as the cells differentiated towards the endothelial cell lineage. Notably, we observed two distinct patterns of γH2AX foci: the typical discrete γH2AX foci, which colocalize with the transcriptionally permissive chromatin mark H3K4me3, and the less well-characterized clustered γH2AX regions, which were only observed in intermediate progenitor cells. Next, we explored responses of mESCs to γ-radiation (137Cs). Following exposure to γ-radiation, mESCs showed a reduction in cell viability and increased γH2AX foci, indicative of radiosensitivity. Despite irradiation, surviving mESCs retained their differentiation potential. To further exemplify our findings, we investigated neural stem progenitor cells (NSPCs). Similar to mESCs, NSPCs displayed clustered γH2AX foci associated with progenitor cells and discrete γH2AX foci indicative of embryonic stem cells or differentiated cells. In conclusion, our findings demonstrate that γH2AX serves as a versatile marker of DSBs and may have a role as a biomarker in stem cell differentiation. The distinct patterns of γH2AX foci in differentiating mESCs and NSPCs provide valuable insights into DNA repair dynamics during differentiation, shedding light on the intricate balance between genomic integrity and cellular plasticity in stem cells. Finally, the clustered γH2AX foci observed in intermediate progenitor cells is an intriguing feature, requiring further exploration.

Omental torsion: diagnostic challenge in patients with sclerosing cholangitis and inflammatory bowel disease - case report.

Introduction and importance: The omentum appears as an apron-like extension of the peritoneum. Case presentation: A 30-year-old male patient, presented to the emergency department with the chief complaints of acute nonradiating pain localized in the right-side abdomen for the past 3 days. The patient had a past medical history of sclerosing cholangitis (SC) with inflammatory bowel disease (IBD). The patient reported the pain as persistent, pressure-like, and moderate. The patient also had a low-grade fever and nausea at the time of admission. On examination, the vital signs were found as normal. The patient reported that the abdominal pain gets exacerbated after the meals, and increase in physical activity and movement. Due to the patient's complaints and history of SC and IBD, these were considered as the possible diagnosis. After the diagnostic procedures, the patient was finally diagnosed with OT. Clinical discussion: This report presents a case of a patient suffering from omental torsion having history of SC and IBD. During the laparoscopic procedure, the diagnosis of omental torsion was confirmed. To our knowledge, no case report of omental torsion with IBD and SC is published in the literature. Conclusion: This seems to be a major diagnostic challenge as patients with IBD almost resembles the same clinical signs and symptoms as in the omental torsion. The possibility of misdiagnosis and delayed diagnosis could result in the unfavorable outcome. Therefore, the healthcare fraternities are advised to include the rare diseases such as OT as the differential diagnosis.

Phytochemicals: Alternative for Infertility Treatment and Associated Conditions.

Infertility and obstetric complications have become global health issues in the past few years. Infertility is defined as the inability of a couple to conceive even after twelve months or more of regular and unprotected intercourse. According to WHO data published in the year 2020, 186 million people have infertility globally. Factors leading to infertility are variable in both males and females. But some common factors include smoking, alcohol consumption, obesity, and stress. Various synthetic drugs and treatment options are available that are effective in treating infertility, but their prolonged usage produces various unwanted adverse effects like hot flashes, mood swings, headaches, and weight gain. In extreme cases, these may also lead to the development of anxiety and depression. Herbal remedies have gained a lot of popularity over the years, and people's inclination toward them has increased all over the world. The prime reason is that these show significant therapeutic efficacy and have fewer side effects. The therapeutic efficacy of plants can be attributed to the presence of diverse phytochemical classes of constituents like alkaloids, flavonoids, and volatile oils. These secondary metabolites, or phytomolecules, can be used to develop herbal formulations. The review highlights the applications and mechanisms of action of various phytochemicals for treating infertility. Also, it focuses on the various future prospects associated with it.

Characterizing a CT esophagram protocol after flexible endoscopic diverticulotomy for Zenker's diverticulum: a retrospective series.

Background: Flexible endoscopic cricopharyngeal myotomy and septotomy offer a minimally invasive transluminal option for the treatment of symptomatic Zenker's diverticulum (ZD). There is currently no consensus regarding postoperative follow-up imaging. We suggest a standardized computed tomography (CT) esophagram protocol for radiographic evaluation of postoperative findings. Methods: Single center retrospective analysis of patients with symptomatic ZD who underwent flexible endoscopic diverticulotomy and postoperative imaging with CT esophagram from January 2015 to March 2020. An experienced radiologist blinded to the initial imaging reports prospectively interpreted all CT esophagram findings, in order to minimize bias. Results: Twenty-one patients underwent CT esophagram following flexible endoscopic diverticulotomy for ZD. Diverticulotomy was technically successful in all patients. Most common findings on imaging included: atelectasis (13/21; 62%), persistent esophageal diverticulum (7/21; 33%), pneumomediastinum (3/21; 14%), aspiration (2/21; 10%), and extraluminal air and contrast extravasation consistent with focal esophageal perforation (1/21; 5%). Conclusions: We describe a standardized, simple, and accessible CT esophagram protocol for postoperative imaging of patients with post-flexible endoscopic cricopharyngeal myotomy and septotomy for ZD. CT esophagram facilitates a definitive exclusion of focal esophageal perforation as a postoperative complication of flexible endoscopic diverticulotomy by ruling out extraluminal air and contrast extravasation.

Racial differences in the presentation and outcomes of diffuse large B-cell lymphoma in the United States.

BACKGROUND: Diffuse large B-cell lymphoma (DLBCL) is often cured with standard chemoimmunotherapy, but there is great heterogeneity in presentation and outcomes. METHODS: By using Surveillance, Epidemiology, and End Results (SEER) data from 13 registries across the United States, the authors examined differences in incidence and survival for DLBCL by race. International Classification of Diseases for Oncology, third edition histology codes 9678, 9679, 9680, and 9684 were used to identify cases. RESULTS: From 1992 to 2007, 38,522 cases of DLBCL were recorded in SEER. Sixty-five percent of black patients compared with 37% of white patients presented at age ≤ 60 years, 52% of blacks compared with 44% of whites presented with stage III/IV disease, and 31% of black versus 24% of white patients presented with B symptoms (all P < .001). Although survival improved by era of diagnosis for all races (log rank P < .001), 2-year relative survival rates were better for women than men (61% vs 58%, P < .001) and white than black patients (60% vs 50%, P < .001). Black race, male sex, age at diagnosis >60, advanced stage, and B symptoms at diagnosis were predictors of worse survival (P < .001). CONCLUSIONS: Black patients with DLBCL in the United States present at younger age, more advanced stage, and have inferior survival. Epidemiological studies that examine the biological variants of DLBCL in concert with race are needed to elucidate the etiology of these disparities.

Development of Tetrahydroindazole-Based Potent and Selective Sigma-2 Receptor Ligands.

The sigma-2 receptor has been shown to play important roles in a number of important diseases, including central nervous system (CNS) disorders and cancer. However, mechanisms by which sigma-2 contributes to these diseases remain unclear. The development of new sigma-2 ligands that can be used to probe the function of this protein and potentially as drug discovery leads is therefore of great importance. Herein we report the development of a series of tetrahydroindazole compounds that are highly potent and selective for sigma-2. Structure-activity relationship data were used to generate a pharmacophore model that summarizes the common features present in the potent ligands. Assays for solubility and microsomal stability showed that several members of this compound series possess promising characteristics for further development of useful chemical probes or drug discovery leads.

Practical synthesis of a chromene analog for use as a retinoic acid receptor alpha antagonist lead compound.

Retinoic acid receptor alpha (RARα) selective compounds may guide the design of drugs that can be used in conjunction with hormonal adjuvant therapy in the treatment of breast cancer. Herein we report a modified synthesis of a known RARα antagonist, 2-fluoro-4-[[[8-bromo-2,2-dimethyl-4-(4-methylphenyl)chroman-6-yl]carbonyl]amino]benzoic acid and a synthesis of its unknown, desfluoro analog, 4-[[[8-bromo-2,2-dimethyl-4-(4-methylphenyl)chroman-6-yl]carbonyl]amino]benzoic acid. The modified route allows for facile reaction workups, increased yields, lower cost and incorporates a green alternative step. Structure-activity relationship studies determined through functional cell-based assays, demonstrated antagonism to RARα for both compounds. Molecular modeling within the RARα binding pocket was used to compare binding interactions of the desfluoro analog to a known RAR antagonist.

Exploring risk factors for follicular lymphoma.

Follicular lymphoma (FL) is an indolent malignancy of germinal center B cells with varied incidence across racial groups and geographic regions. Improvements in the classification of non-Hodgkin lymphoma subtypes provide an opportunity to explore associations between environmental exposures and FL incidence. Our paper found that aspects of Western lifestyle including sedentary lifestyle, obesity, and diets high in meat and milk are associated with an increased risk of FL. Diets rich in fruits and vegetables, polyunsaturated fatty acids, vitamin D, and certain antioxidants are inversely associated with FL risk. A medical history of Sjogren's syndrome, influenza vaccination, and heart disease may be associated with FL incidence. Associations between FL and exposure to pesticides, industrial solvents, hair dyes, and alcohol/tobacco were inconsistent. Genetic risk factors include variants at the 6p21.32 region of the MHC II locus, polymorphisms of the DNA repair gene XRCC3, and UV exposure in individuals with certain polymorphisms of the vitamin D receptor. Increasing our understanding of risk factors for FL must involve integrating epidemiological studies of genetics and exposures to allow for the examination of risk factors and interactions between genes and environment.

Incidence patterns and outcomes for hodgkin lymphoma patients in the United States.

Hodgkin lymphoma (HL) demonstrates heterogenous histologic findings, clinical presentation, and outcomes. Using the United States Surveillance, Epidemiology, and End Results (SEER) data we examined relationships between patient characteristics, clinical features at diagnosis, and survival in HL patients. From 2000 to 2007, 16,710 cases were recorded in 17 SEER registries. Blacks and Asians had low incidence (black/white incidence rate ratio (IRR) 0.86, P < .01; Asian/white IRR 0.43, P < .01). The bimodal pattern of incidence was less prominent for black males. Asians and Blacks presented at a mean age of 38 years compared to 42 years for Whites (P < .001). Race was a predictor for survival with HR of 1.19 (95% CI 1.11-1.28) for Blacks. Age was the most important predictor of survival (HR for patients ≥45 years 5.08, 95% CI 4.86-5.31). These current patterns for presentation and outcomes of HL help to delineate key populations in order to explore risk factors for HL and strategies to improve treatment outcomes.

Clinical, molecular, and environmental risk factors for hodgkin lymphoma.

Epidemiological studies suggest unique occurrence patterns of Hodgkin lymphoma (HL) worldwide. In most Western countries there is a clear bimodal age distribution with an early peak in young adults followed by a second peak in older adults, particularly among males. In the Middle East and Asia, HL is more common in early childhood. There also are marked racial differences in the presentations of HL and HL subtypes, and particular single nucleotide polymorphisms (SNPs) have been identified as etiological factors suggesting that gene-gene and gene-environment interactions are involved. Personal health choices such as exercise and smoking may modify an individual's chances of developing HL. Numerous studies highlight the impact that exposure to Epstein-Barr virus and other environmental factors have on HL risk. Understanding the relative importance of each of these findings and their links to HL development and survival will help clinical researchers expand curative therapies and create preventative strategies for HL.

Racial differences in the presentation and outcomes of chronic lymphocytic leukemia and variants in the United States.

BACKGROUND: Chronic lymphocytic leukemia (CLL) is the most common form of adult leukemia in the United States, and prolymphocytic leukemia (PLL) is a related, rare chronic lymphoproliferative disorder. METHODS: Using the United States Surveillance, Epidemiology and End Results (SEER) data from 13 registries, we examined differences in incidence and survival for CLL, small lymphocytic lymphoma (SLL) and PLL by race. International Classification of Diseases for Oncology 3(rd) edition histology codes 9670, 9823, and 9632-34 were used to identify cases. RESULTS: From 1992 to 2007, 30,622 cases of CLL/SLL and 268 cases of PLL were recorded. Males had higher incidence than females (male-to-female incidence rate ratio CLL/SLL 1.89, 95% confidence interval (CI) 1.85-1.94 and PLL 2.47, 95%CI 1.90-3.20). Black patients were diagnosed at younger age compared to white patients (mean age at diagnosis for white versus black patients for CLL/SLL, 70 versus 67 years, P < .001; for PLL, 71 versus 61 years, P < .001). Greater proportion of black patients with SLL presented with B symptoms, extranodal primary site, and advanced disease compared to white patients (P = .003, P = .012, and P = .009 respectively). White patients with CLL/SLL had better survival rates than black patients (5-year relative survival rate 77.1% versus 63.9%, P < .01). In univariate Cox regression models, black race, male gender, age at diagnosis > 65 years, advanced stage, and B-symptoms were predictors of worse survival (P < .01) among CLL/SLL patients. CONCLUSIONS: Black patients with CLL/SLL and PLL present at younger age and black patients with CLL/SLL have worse survival than white patients. Epidemiological studies examining the biological variants of these diseases in concert with race are needed to elucidate the etiology of these disparities.