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Several prospective studies report improved outcomes with pretreatment nutrition interventions prior to radiation therapy for head and neck cancer (HNC), but none have assessed similar interventions before surgery for HNC.POINT, a pilot randomized controlled trial, was conducted to evaluate a multimodal nutrition intervention. Patients undergoing primary surgery with free flap reconstruction for HNC were randomly assigned to the control arm or a preoperative multimodal nutrition intervention.POINT included 49 patients. Nutrition risk scores did not change significantly for either the intervention or control group. Control patients had a significant decrease in body weight in the preoperative period (p 0.001). Conversely, weight among intervention patients did not significantly decrease (p = 0.680). The intervention mitigated weight loss in patients with dysphagia (p = 0.001).Preoperative nutrition optimization shows potential to reduce weight loss normally experienced by patients with head and neck cancer prior to surgical extirpation, especially among those with subjective dysphagia.

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ImportanceTimely initiation of postoperative radiation therapy (PORT) is associated with reduced recurrence rates and improved overall survival in patients with head and neck squamous cell carcinoma (HNSCC). Measurement of the association of social-ecological variables with PORT delays is lacking.ObjectiveTo assess individual and community-level factors associated with PORT delay among patients with HNSCC.Design, Setting, and ParticipantsThis prospective cohort study carried out between September 2018 and June 2022 included adults with untreated HNSCC who were enrolled in a prospective registry at a single academic tertiary medical center. Demographic information and validated self-reported measures of health literacy were obtained at baseline visits. Clinical data were recorded, and participant addresses were used to calculate the area deprivation index (ADI), a measure of community-level social vulnerability. Participants receiving primary surgery and PORT were analyzed. Univariable and multivariable regression analysis was performed to identify risk factors for PORT delays.ExposuresSurgical treatment and PORT.Main Outcomes and MeasuresThe primary outcome was PORT initiation delay (>42 days from surgery). Risk of PORT initiation delay was evaluated using individual-level (demographic, health literacy, and clinical data) and community-level information (ADI and rural-urban continuum codes).ResultsOf 171 patients, 104 patients (60.8%) had PORT delays. Mean (SD) age of participants was 61.0 (11.2) years, 161 were White (94.2%), and 105 were men (61.4%). Insurance was employer-based or public among 65 (38.5%) and 75 (44.4%) participants, respectively. Mean (SD) ADI (national percentile) was 60.2 (24.4), and 71 (41.8%) resided in rural communities. Tumor sites were most commonly oral cavity (123 [71.9%]), with 108 (63.5%) classified as stage 4 at presentation. On multivariable analysis, a model incorporating individual-level factors with health literacy in addition to community-level factors was most predictive of PORT delay (AOC= 0.78; R2, 0.18).Conclusions and RelevanceThis cohort study provides a more comprehensive assessment of predictors of PORT delays that include health literacy and community-level measures. Predictive models that incorporate multilevel measures outperform models with individual-level factors alone and may guide precise interventions to decrease PORT delay for at-risk patients with HNSCC.

We investigated the potential of combining the hypoglycemic drug metformin (MET) and the antiepileptic drug valproic acid (VPA), which act via different biochemical pathways, to provide enhanced antitumor responses in prostate cancer. Prostate cancer cell lines (LNCaP and PC-3), normal prostate epithelial cells (PrEC), and patient-derived prostate tumor explants were treated with MET and/or VPA. Proliferation and apoptosis were assessed. The role of p53 in response to MET + VPA was assessed in cell lines using RNAi in LNCaP (p53+) and ectopic expression of p53 in PC-3 (p53−). The role of the androgen receptor (AR) was investigated using the AR antagonist enzalutamide. The combination of MET and VPA synergistically inhibited proliferation in LNCaP and PC-3, with no significant effect in PrEC. LNCaP, but not PC-3, demonstrated synergistic intrinsic apoptosis in response to MET + VPA. Knockdown of p53 in LNCaP (p53+, AR+) reduced the synergistic apoptotic response as did inhibition of AR. Ectopic expression of p53 in PC-3 (p53−, AR−) increased apoptosis in response to MET + VPA. In patient-derived prostate tumor explants, MET + VPA also induced a significant decrease in proliferation and an increase in apoptosis in tumor cells. In conclusion, we demonstrate that MET + VPA can synergistically kill more prostate cancer cells than either drug alone. The response is dependent on the presence of p53 and AR signaling, which have critical roles in prostate carcinogenesis. Further in vivo/ex vivo preclinical studies are required to determine the relative efficacy of MET + VPA as a potential treatment for prostate cancer. Mol Cancer Ther; 16(12); 2689–700. ©2017 AACR.

Legends of supplementary Figure S1, S2, S3, S4, and S5.

S1: Comparison of the Incucyte FLR and Operetta High Content Imaging System for detection of apoptosis in PC-3 cells induced by Paclitaxel. S2: Nuclear fragmentation index of PC-3 cells in the presence and absence of ectopically expressed p53 in response to MET and VPA. S3: p53 knock-down in LNCaP cells using siRNA. S4: Efficiency of GFP-p53 and GFP-only plasmid transfection in PC-3 cells. S5: Apoptosis in PC-3 cells in response to MET and VPA in the presence and absence of Enzalutamide.

Background: Mindfulness meditation has been shown to alleviate pain and may be an appealing adjunctive pain management option. Objective: To compare measures of pain, mindfulness, and opioid usage, and collect evaluative feedback among patients undergoing septorhinoplasty with and without guided meditation. Methods: Patients undergoing septorhinoplasty were randomized to online-guided meditation postoperative days 0-3 versus standard care; all received the same pain medications. Primary outcome measures included pain intensity, opioid consumption, mindfulness scores, and evaluative feedback. Results: Twenty-one patients received guided meditation and 24 received standard care. No significant difference in opioid consumption or pain scores was seen with the exception of higher opioid use in patients with intranasal splints in the standard care group. Twenty out of 21 patients provided evaluative feedback; all recommended mindfulness meditation to friends undergoing nasal surgery, 90% reported it was beneficial, 85% believed it eased pain/discomfort, and 80% believed it aided with sleep. Conclusion: Although no objective difference was found in opioid consumption or pain scores, most patients reported that guided mindfulness meditation was beneficial to their recovery following septorhinoplasty.

Cyclin-dependent kinase 2 (CDK2) has been garnering considerable interest as a target to develop new cancer treatments and to ameliorate resistance to CDK4/6 inhibitors. However, a selective CDK2 inhibitor has yet to be clinically approved. With the desire to discover novel, potent, and selective CDK2 inhibitors, the phenylsulfonamide moiety of our previous lead compound 1 was bioisosterically replaced with pyrazole derivatives, affording a novel series of N,4-di(1H-pyrazol-4-yl)pyrimidin-2-amines that exhibited potent CDK2 inhibitory activity. Among them, 15 was the most potent CDK2 inhibitor (Ki = 0.005 µM) with a degree of selectivity over other CDKs tested. Meanwhile, this compound displayed sub-micromolar antiproliferative activity against a panel of 13 cancer cell lines (GI50 = 0.127–0.560 μM). Mechanistic studies in ovarian cancer cells revealed that 15 reduced the phosphorylation of retinoblastoma at Thr821, arrested cells at the S and G2/M phases, and induced apoptosis. These results accentuate the potential of the N,4-di(1H-pyrazol-4-yl)pyrimidin-2-amine scaffold to be developed into potent and selective CDK2 inhibitors for the treatment of cancer. Refereed/Peer-reviewed

Peripersonal space (PPS) is frequently defined as a plastic, pragmatic and goal-directed multisensory buffer that connects the brain-body with its immediate environment. While such characterisations indicate that peripersonal spatiality is profoundly embodied and enactive, comparatively few attempts have aimed to systematically synthesise PPS literature with compatible phenomenological accounts of lived space provided by Heidegger and Merleau-Ponty. Moreover, in traditional cognitive neuroscience, neurophysiological activity is thought to map onto discrete ‘cognitive correlates’. In contemporary 4E approaches to cognition, however, phenomenology-derived notions such as ‘pre-reflective cognition’ and ‘motor-intentionality’ frequently appear, yet their neural correlates may be comparatively difficult to pin down. Pre-reflectively, agents seemingly do not thematise spatial properties as operationalised in key experimental paradigms (e.g., spatial rotation tasks) but are instead inherently spatially embedded within the world. To refine this distinction, I survey how tools co-determine this distinctly spatial ‘world-embeddedness’ using a neurophenomenological methodology (Varela, Journal of Consciousness Studies, 3(4), 330–349, 1996). Specifically, I conduct two neurophenomenological analyses of tool-perception and tool-use, examining both how distance modulates affordance-perception and how tool-use remaps bodily space via the withdrawal of tools from intentional-objects into co-constituting motor-intentionality itself. I conclude by briefly distinguishing this interpretation of spatial cognition from cognitivist frameworks. Thereafter, I briefly highlight the temporal scaffolding underlying PPS while conceptually grounding my account within Embodied Simulation Theory (Gallese, Reti, Saperi, Linguaggi, (1), 31–46, 2018). What is at stake is thus both an explicitly embodied-enactive account of bodily space that is qualitative and situational instead of quantitative and positional, as well as a viable, interdisciplinary strategy for unifying pre-reflective cognition with neurophysiological data.

Background Chronic Obstructive Pulmonary Disease is characterised by declining lung function and a greater oxidative stress burden due to reduced activity of antioxidant enzymes such as Glutathione Peroxidase 1. Objectives The extent to which drugs may contribute to this compromised activity is largely unknown. An integrative drug safety model explores inhibition of Glutathione Peroxidase 1 by drugs and their association with chronic obstructive pulmonary disease adverse drug events. Methods In silico molecular modelling approaches were utilised to predict the interactions that drugs have within the active site of Glutathione Peroxidase 1 in both human and bovine models. Similarities of chemical features between approved drugs and the known inhibitor tiopronin were also investigated. Subsequently the Food and Drug Administration Adverse Event System was searched to uncover adverse drug event signals associated with chronic obstructive pulmonary disease. Results Statistical and molecular modelling analyses confirmed that the use of several registered drugs, including acetylsalicylic acid and atenolol may be associated with inhibition of Glutathione Peroxidase 1 and chronic obstructive pulmonary disease. Conclusion The integration of molecular modelling and pharmacoepidemological data has the potential to advance drug safety science. Ongoing review of medication use and further pharmacoepidemiological and biological analyses are warranted to ensure appropriate use is recommended. Graphical Abstract

OBJECTIVE. Consumer wearables, such as the Apple Watch or Fitbit devices, have become increasingly commonplace over the past decade. The application of these devices to health care remains an area of significant yet ill-defined promise. This review aims to identify the potential role of consumer wearables for the monitoring of otolaryngology patients. DATA SOURCES. PubMed. REVIEW METHODS. A PubMed search was conducted to identify the use of consumer wearables for the assessment of clinical outcomes relevant to otolaryngology. Articles were included if they described the use of wearables that were designed for continuous wear and were available for consumer purchase in the United States. Articles meeting inclusion criteria were synthesized into a final narrative review. CONCLUSIONS. In the perioperative setting, consumer wearables could facilitate prehabilitation before major surgery and prediction of clinical outcomes. The use of consumer wearables in the inpatient setting could allow for early recognition of parameters suggestive of poor or declining health. The real-time feedback provided by these devices in the remote setting could be incorporated into behavioral interventions to promote patients’ engagement with healthy behaviors. Various concerns surrounding the privacy, ownership, and validity of wearable-derived data must be addressed before their widespread adoption in health care. IMPLICATIONS FOR PRACTICE. Understanding how to leverage the wealth of biometric data collected by consumer wearables to improve health outcomes will become a high-impact area of research and clinical care. Well-designed comparative studies that elucidate the value and clinical applicability of these data are needed.

To optimize the delivery of multimodal analgesia to patients undergoing major head and neck oncologic surgeries.Pilot study included patients enrolled to receive either scheduled acetaminophen and as-needed opioids (control group) or scheduled acetaminophen, gabapentin, ketorolac, and as-needed opioids (experimental group). RCT, a hybrid type 1 effectiveness-implementation pragmatic trial, was designed to test the effectiveness of the intervention. Arm A received scheduled acetaminophen and as-needed opioids. Arm B received scheduled gabapentin, ketorolac, a regional nerve block at the free tissue donor site, scheduled acetaminophen and as-needed opioids.Pilot: Thirty-one patients undergoing major head and neck surgery were enrolled. Mean MMEs administered in control group (n = 15) was 251.60 mg (SD = 224.57 mg); mean MMEs in Experimental group (n = 16) was 195.78 mg (SD = 131.08 mg), p = 0.401. LOS was 8.0 days in control versus 7.0 days in experimental group (p = 0.054). RCT: Interim analysis for safety and futility was planned during trial's design after 30 patients (n = 14 Arm A, and n = 16 Arm B). Mean MMEs administered were 135.1 mg in Arm A, (SD = 86.0 mg) versus mean MME of 51.3 mg in Arm B (SD = 43.3 mg, (p 0.05)). Given clear superiority results, the trial was prematurely terminated. Functional pain scores, LOS, and complications were similar between the arms (p 0.05). Variability of mean MME was compared before and after implementation of the management protocols: SD in RCT#1 was 181.46 mg versus 124.6 mg in RCT#2.Multimodal analgesia significantly reduced the need for opioids in patients undergoing major head and neck surgery.1, Randomized Clinical Trial Laryngoscope, 2022.

Burnout has been previously assessed in head and neck microvascular reconstructive surgeons (HNMVS), but not in the context of modifiable workplace factors.Anonymous, cross-sectional survey. The Abbreviated Maslach Burnout Inventory - Human Services Survey for Medical Personnel (aMBI-HSS) was utilized to assess emotional exhaustion (EE), depersonalization (DP), and personal achievement (PA). Modifiable risk factors were also evaluated.High risk of burnout by EE, DP, and PA was demonstrated in 24%, 9%, and 27% of respondents, respectively. EE was associated with10% dedicated research time, lack of autonomy over clinic schedule, inadequate inpatient support, and lack of supportive clinical partner. DP was associated with3 operative days, difficulty balancing academic commitments, and lack of supportive clinical partner. Dedicated research time and two or fewer days of block time were protective.Burnout was associated with several modifiable workplace factors. Addressing these may prevent moderate to severe burnout in HNMVS.

Background: Olfactory dysfunction (OD) is an early symptom of Alzheimer’s disease (AD). However, olfactory testing is not commonly performed to test OD in the setting of AD. Objective: This work investigates objective OD as a non-invasive biomarker for accurately classifying subjects as cognitively unimpaired (CU), mild cognitive impairment (MCI), and AD. Methods: Patients with MCI (n = 24) and AD (n = 24), and CU (n = 33) controls completed two objective tests of olfaction (Affordable, Rapid, Olfactory Measurement Array –AROMA; Sniffin’ Sticks Screening 12 Test –SST12). Demographic and subjective sinonasal and olfaction symptom information was also obtained. Analyses utilized traditional statistics and machine learning to determine olfactory variables, and combinations of variables, of importance for differentiating normal and disease states. Results: Inability to correctly identify a scent after detection was a hallmark of MCI/AD. AROMA was superior to SST12 for differentiating MCI from AD. Performance on the clove scent was significantly different between all three groups. AROMA regression modeling yielded six scents with AUC of the ROC of 0.890 (p

Background Ambulatory surgery presents unique challenges regarding adequate pain management and education. Studies have documented issues with transfer of information and patient comfort. Our objective was to explore perioperative nurses’ perspectives of current practices and challenges with pain management and education. Materials and methods We used a qualitative descriptive design and conducted four focus group interviews, with 24 total participants from two perioperative areas of an academic medical center, using a standardized script. Using qualitative analysis software, two investigators reviewed the data and coded major themes and subthemes. The consolidated criteria for reporting qualitative studies guidelines were followed for reporting the data. Results We identified four major themes impacting current perioperative pain management and education practices: communication among the perioperative care team, sources of nurses’ frustrations in the perioperative setting, patient expectations for pain, and nurse-driven pain management and education. Nurses highlighted their work became easier with adequate information transfer and trust from physicians. Frustrations stemmed from surgeon, system, and patient factors. Nurses often use their clinical experience and judgment in managing patients throughout the perioperative period. Furthermore, nurses felt patients have limited pain education and stressed education throughout the surgical care pathway could improve overall care. Conclusions Perioperative pain management, assessment, and education practices are inconsistent, incomplete, and sources of frustrations according to participants. Participant experiences highlight the need for improved and standardized models. Patient pain education should use a multidisciplinary approach, beginning at the point of surgery scheduling and continuing through postoperative follow-up.

Study Design Retrospective chart review. Objective Restoration of premorbid occlusion is a key goal in the treatment of mandibular fractures. Placement of the patient in maxillomandibular fixation (MMF) is performed during mandibular fracture repair to help establish occlusion. A number of techniques are available to achieve MMF. We sought to examine trends in MMF technique at our institution. Methods A retrospective chart review was conducted to evaluate patients who underwent surgical treatment of mandibular fractures between January 1, 2011 and March 31, 2021. Data including fracture characteristics, mechanism of injury, patient demographics, complication rates, and MMF technique utilized were collected. Results One hundred sixty-three patients underwent MMF (132 males). The most common etiology of fracture was assault (34%). There was an increasing preference for rapid MMF techniques over time, as opposed to standard Erich arch bars. No significant difference in obtaining adequate fracture reduction as determined by postoperative imaging or complications were noted between those who underwent MMF with newer rapid techniques vs traditional MMF techniques. Conclusions Our institution has demonstrated changing trends in the technique utilized for establishing occlusion intraoperatively, more recently favoring rapid MMF techniques, with similar rates of complications and ability to adequately reduce fractures.

Background The coronavirus disease 2019 pandemic has led to increased telemedicine visits. This study examines current preferences and barriers for telemedicine among patients with head and neck cancer. Methods Single institution retrospective analysis of 64 patients scheduling visits with the head and neck surgical oncology clinic at a tertiary academic medical center. Data were collected detailing patient preferences and barriers regarding telemedicine appointments. Patients electing to participate in telemedicine were compared to those preferring in‐person appointments. Results Most patients (68%) were not interested in telemedicine. Preference for in‐person examination was the most common reason for rejecting telemedicine, followed by discomfort with or limited access to technology. Patients elected telemedicine visits to avoid infection and for convenience. Conclusions When given a choice, patients with head and neck cancer preferred in‐person visits over telemedicine. Although telemedicine may improve health care access, patient preferences, technology‐related barriers, and limitations regarding cancer surveillance must be addressed moving forward.

The regulation of vitamin D

Refereed/Peer-reviewed

Introduction The number of congenital syphilis (CS) cases in Arizona quadrupled from an average of 14 cases annually before 2017 to 61 cases in 2018, and a statewide outbreak was declared. The Arizona Department of Health Services (ADHS) analyzed statewide surveillance data to identify missed opportunities for prevention and collaborated with the Arizona Health Care Cost Containment System (AHCCCS) to inform response activities. Methods ADHS developed a metric to identify missed opportunities for CS prevention during pregnancy by using medical records, vital records, and case investigation notes for all mothers of infants born with CS from January 1, 2017, through June 30, 2018. AHCCCS conducted a cost-effectiveness analysis to calculate the effect of increasing perinatal syphilis screening. Results Arizona had 57 cases of CS during the study period, of which 17 (29.8%) could have been prevented through third-trimester screening for women who were in prenatal care but screened late (n = 9), were infected after their first prenatal visit screen (n = 7), or were reinfected after an initial reactive syphilis test and appropriate treatment and not rescreened (n = 1). The estimated net cost of combining the additional primary (screening) and secondary (treatment) costs of a third-trimester screen for all pregnant AHCCCS members and the estimated total per-year savings of all newborn hospitalizations was $527. Practice Implications Third-trimester syphilis screening could prevent CS in regions where syphilis transmission is high. Partnering with health insurance agencies to evaluate the cost effectiveness of screening recommendations may improve the accuracy of the estimate of the potential cost savings by using insurance agency–specific data for the population at risk for CS.

Objectives: First-line treatment of chronic rhinosinusitis includes topical corticosteroids aimed at decreasing inflammation of sinonasal mucosa. No guidelines exist regarding the effect of head position during administration of corticosteroids. We hypothesize certain positions enhance delivery to the paranasal sinuses, with further improvement in delivery after sinus surgery. Methods: A systematic review of the literature was conducted using Medline Ovid, Embase, Scopus, and Cochrane databases. All studies evaluating intranasal medications administered in 2 or more head positions were included. Study population, head position(s), method/volume of delivery, and outcome metrics were recorded. Results: Twenty-four studies compared head positions and their role in distribution of intranasal medication. Of 12 papers studying surgically naive subjects, 6 found improvement in delivery to specific sinonasal regions (middle meatus; lateral, superior, or posterior nasal cavity) and/or symptomatic improvement, in the lying head back (LHB) or head down and forward (HDF) positions, but only 3 reached statistical significance. Of 12 papers studying surgically altered patients, 10 found delivery improved in the HDF, LHB, and head forward 45° or 90° positions. Of 5 studies of extended frontal sinus procedures (Draf IIb/III), a majority found distribution to the frontal sinus improved with the head forward 90° position. Patients found the HDF position most uncomfortable. Conclusions: Studies found no statistically significant difference in distribution to unoperated sinuses among different head positions. A minority of studies supported the use of the LHB and HDF positions. This suggests that in surgically naive patients, intranasal corticosteroid delivery to sinonasal regions and/or symptomatic improvement may be best achieved with the sinuses positioned inferior to the delivery device. Surgery improved distribution to the paranasal sinuses regardless of head position, although tilting the head forward 90° was particularly effective in delivery to the frontal sinus after extended frontal sinus procedures.

While a comprehensive booth audiogram is the gold standard for diagnosis of hearing loss, access to this may not be available in remote and low resource settings. The aims of this study were to validate a tablet-based audiometer in a tertiary medical center in India and explore its capacity in improving access to hearing healthcare. Subjects presenting to Ear–Nose–Throat clinics for conventional booth audiometry testing were recruited for subsequent tablet-based audiometric testing. Testing with the tablet was conducted in a non-sound-treated hospital clinic room. Bilateral air and bone conduction hearing threshold data from 250 through 4000 Hz were validated against conventional booth audiometry. In addition, a small feasibility study was conducted in rural clinics. 70 participants (37 adults and 33 children between the ages 5–18) were assessed. 69% were male, with a mean age of 29.7 years. Sensitivity and specificity for the tablet were 89% (95% CI 80–94%) and 70% (95% CI 56–82%), respectively. While median differences in air conduction thresholds between conventional and tablet audiograms showed statistical significance at 250, 500, and 1000 Hz (p

Objectives: (1) To investigate the state of diversity and inclusion initiatives in otolaryngology–head and neck surgery (OHNS) as compared to general surgery and (2) assess their effects on female representation in these programs. Methods: The websites of OHNS residency programs, general surgery residency programs, and their associated academic medical institutions were indexed for content related to diversity and inclusion (D&I) initiatives. Gender data were gathered and used as a proxy for identity diversity. Results: All programs surveyed (N = 198) have D&I programs at the institutional level and have an office of D&I (or equivalent program). However, only 18% of general surgery programs and 19% of otolaryngology programs have additional department-level D&I initiatives. There was an increase in the proportion of female residents across all residency programs if the program mentioned D&I on their website (44% vs 38%, P = .004) and if the program reported a D&I initiative (45% vs 38%, P < .001). Conclusion: Despite the ACGME’s recent emphasis on the importance of recruiting and retaining a diverse physician workforce, the minority of otolaryngology residency programs advertise any concerted, department-level efforts toward increasing D&I at their residency program. General surgery programs have a significantly higher proportion of female department chairs and higher mean proportion of female residents when compared to OHNS. Programs that mention the diversity of their residents or faculty on the program website and programs with their own D&I initiatives have a higher mean proportion of female residents.

(1) Describe the existing head and neck cancer health disparities literature. (2) Contextualize these studies by using the NIMHD research framework (National Institute on Minority Health and Health Disparities). (3) Explore innovative ideas for further study and intervention.Ovid MEDLINE, Embase, Web of Science, and Google Scholar.Databases were systematically searched from inception to April 20, 2020. The PRISMA checklist was followed (Preferred Reporting Items for Systematic Reviews and Meta-analyses). Two authors reviewed all articles for inclusion. Extracted data included health disparity population and outcomes, study details, and main findings and recommendations. Articles were also classified per the NIMHD research framework.There were 148 articles included for final review. The majority (n = 104) focused on health disparities related to at least race/ethnicity. Greater than two-thirds of studies (n = 105) identified health disparities specific to health behaviors or clinical outcomes. Interaction between theThere has been extensive study of health disparities for head and neck cancer, largely focusing on individual patient factors or health care access and quality. This review identifies gaps in this research, with large numbers of retrospective database studies and little discussion of potential contributors and explanations for these disparities. We recommend shifting research on disparities upstream toward a focus on community and societal factors, rather than individual, and an evaluation of interventions to promote health equity.

Refereed/Peer-reviewed Cyclin-dependent kinase 3 (CDK3) is a major player driving retinoblastoma (Rb) phosphorylation during the G₀/G₁ transition and in the early G₁ phase of the cell cycle, preceding the effects of CDK4/cyclin D, CDK6/cyclin D, and CDK2/cyclin E. CDK3 can also directly regulate the activity of E2 factor (E2F) by skipping the role of Rb in late G1, potentially via the phosphorylation of the E2F1 partner DP1. Beyond the cell cycle, CDK3 interacts with various transcription factors involved in cell proliferation, differentiation, and transformation driven by the epidermal growth factor receptor (EGFR)/rat sarcoma virus (Ras) signaling pathway. The expression of CDK3 is extremely low in normal human tissue but upregulated in many cancers, implying a profound role in oncogenesis. Further evaluation of this role has been hampered by the lack of selective pharmacological inhibitors. Herein, we provide a comprehensive overview about the therapeutic potential of targeting CDK3 in cancer.

The regulation of vitamin D3 actions in humans occurs mainly through the Cytochrome P450 24‐hydroxylase (CYP24A1) enzyme activity. CYP24A1 hydroxylates both 25‐hydroxycholecal-ciferol (25(OH)D3) and 1,25‐dihydroxycholecalciferol (1,25(OH)2D3), which is the first step of vitamin D catabolism. An abnormal status of the upregulation of CYP24A1 occurs in many diseases, including chronic kidney disease (CKD). CYP24A1 upregulation in CKD and diminished activation of vitamin D3 contribute to secondary hyperparathyroidism (SHPT), progressive bone deterioration, and soft tissue and cardiovascular calcification. Previous studies have indicated that CYP24A1 inhibition may be an effective strategy to increase endogenous vitamin D activity and decrease SHPT. This study has designed and synthesized a novel C‐24 O‐methyloxime analogue of vitamin D3 (VD1‐6) to have specific CYP24A1 inhibitory properties. VD1‐6 did not bind to the vitamin D receptor (VDR) in concentrations up to 10−7 M, assessed by a VDR binding assay. The absence of VDR binding by VD1‐6 was confirmed in human embryonic kidney HEK293T cultures through the lack of CYP24A1 induction. However, in silico docking experiments demonstrated that VD1‐6 was predicted to have superior binding to CYP24A1, when compared to that of 1,25(OH)2D3. The inhibition of CYP24A1 by VD1‐6 was also evident by the synergistic potentiation of 1,25(OH)2D3‐mediated transcription and reduced 1,25(OH)2D3 catabolism over 24 h. A further indication of CYP24A1 inhibition by VD1‐6 was the reduced accumulation of the 24,25(OH)D3, the first metabolite of 25(OH)D catabolism by CYP24A1. Our findings suggest the potent CYP24A1 inhibitory properties of VD1‐6 and its potential for testing as an alternative therapeutic candidate for treating SHPT. Refereed/Peer-reviewed

Refereed/Peer-reviewed Deregulation of cyclin-dependent kinase 2 (CDK2) and its activating partners, cyclins A and E, is associated with the pathogenesis of a myriad of human cancers and with resistance to anticancer drugs including CDK4/6 inhibitors. Thus, CDK2 has become an attractive target for the development of new anticancer therapies and for the amelioration of the resistance to CDK4/6 inhibitors. Bioisosteric replacement of the thiazole moiety of CDKI-73, a clinically trialled CDK inhibitor, by a pyrazole group afforded 9 and 19 that displayed potent CDK2-cyclin E inhibition (Ki = 0.023 and 0.001 μM, respectively) with submicromolar antiproliferative activity against a panel of cancer cell lines (GI50 = 0.025–0.780 μM). Mechanistic studies on 19 with HCT-116 colorectal cancer cells revealed that the compound reduced the phosphorylation of retinoblastoma at Ser807/811, arrested the cells at the G2/M phase, and induced apoptosis. These results highlight the potential of the 2-anilino-4-(1-methyl-1H-pyrazol-4-yl)pyrimidine series in developing potent and selective CDK2 inhibitors to combat cancer.