Mechanisms of sensitivity and resistance to CDK4/CDK6 inhibitors in hormone receptor-positive breast cancer treatment.

Cell cycle dysregulation is a hallmark of cancer that promotes eccessive cell division. Cyclin-dependent kinase 4 (CDK4) and cyclin-dependent kinase 6 (CDK6) are key molecules in the G1-to-S phase cell cycle transition and are crucial for the onset, survival, and progression of breast cancer (BC). Small-molecule CDK4/CDK6 inhibitors (CDK4/6i) block phosphorylation of tumor suppressor Rb and thus restrain susceptible BC cells in G1 phase. Three CDK4/6i are approved for the first-line treatment of patients with advanced/metastatic hormone receptor-positive (HR+)/human epidermal growth factor receptor 2-negative (HER2-) BC in combination with endocrine therapy (ET). Though this has improved the clinical outcomes for survival of BC patients, there is no established standard next-line treatment to tackle drug resistance. Recent studies suggest that CDK4/6i can modulate other distinct effects in both BC and breast stromal compartments, which may provide new insights into aspects of their clinical activity. This review describes the biochemistry of the CDK4/6-Rb-E2F pathway in HR+ BC, then discusses how CDK4/6i can trigger other effects in BC/breast stromal compartments, and finally outlines the mechanisms of CDK4/6i resistance that have emerged in recent preclinical studies and clinical cohorts, emphasizing the impact of these findings on novel therapeutic opportunities in BC.

Systemic anticancer therapy for urothelial carcinoma: UK oncologists' perspective.

Urothelial carcinoma (UC) is a common cancer associated with a poor prognosis in patients with advanced disease. Platinum-based chemotherapy has remained the cornerstone of systemic anticancer treatment for many years, and recent developments in the treatment landscape have improved outcomes. In this review, we provide an overview of systemic treatment for UC, including clinical data supporting the current standard of care at each point in the treatment pathway and author interpretations from a UK perspective. Neoadjuvant cisplatin-based chemotherapy is recommended for eligible patients with muscle-invasive bladder cancer and is preferable to adjuvant treatment. For first-line treatment of advanced UC, platinum-eligible patients should receive cisplatin- or carboplatin-based chemotherapy, followed by avelumab maintenance in those without disease progression. Among patients unable to receive platinum-based chemotherapy, immune checkpoint inhibitor (ICI) treatment is an option for those with programmed death ligand 1 (PD-L1)-positive tumours. Second-line or later treatment options depend on prior treatment, and enfortumab vedotin is preferred after prior ICI and chemotherapy, although availability varies between countries. Additional options include rechallenge with platinum-based chemotherapy, an ICI, or non-platinum-based chemotherapy. Areas of uncertainty include the optimal number of first-line chemotherapy cycles for advanced UC and the value of PD-L1 testing for UC.

Ontogeny of Human Liver Aldehyde Oxidase: Developmental Changes and Implications for Drug Metabolism.

Despite the increasing importance of aldehyde oxidase (AO) in the drug metabolism of clinical candidates, ontogeny data for AO are limited. The objective of our study was to characterize the age-dependent AO content and activity in the human liver cytosolic fraction (HLC) and human hepatocytes (HH). HLC (n = 121 donors) and HH (n = 50 donors) were analyzed for (1) AO protein content by quantitative proteomics and (2) enzyme activity using carbazeran as a probe substrate. AO activity showed high technical variability and poor correlation with the content in HLC samples, whereas hepatocyte samples showed a strong correlation between the content and activity. Similarly, AO content and activity showed no significant age-dependent differences in HLC samples, whereas the average AO content and activity in hepatocytes increased significantly (∼20-40-fold) from the neonatal levels (0-28 days). Based on the hepatocyte data, the age at which 50% of the adult AO content is reached (age50) was 3.15 years (0.32-13.97 years, 95% CI). Metabolite profiling of carbazeran revealed age-dependent metabolic switching and the role of non-AO mechanisms (glucuronidation and desmethylation) in carbazeran elimination. The content-activity correlation in hepatocytes improved significantly (R2 = 0.95; p < 0.0001) in samples showing <10% contribution of glucuronidation toward the overall metabolism, confirming that AO-mediated oxidation and glucuronidation are the key routes of carbazeran metabolism. Considering the confounding effect of glucuronidation on AO activity, AO content-based ontogeny data are a more direct reflection of developmental changes in protein expression. The comprehensive ontogeny data of AO in HH samples are more reliable than HLC data, which are important for developing robust physiologically based pharmacokinetic models for predicting AO-mediated metabolism in children.

Dynamic Drop Penetration of Horizontally Oriented Fiber Arrays.

In this experimental study, we combine drop impact into porous media and onto a single fiber to study drop impact into fiber arrays inspired by mammalian fur coats. In our 3D-printed arrays, we vary the packing density, fiber alignment, strand cross-section, and wettability. Drops impact fibers fixed at both ends, penetrating over short periods of time by momentum and laterally spreading throughout the array. Using image analysis, we measure penetration depth and wetted width into the array. Impact Weber number and intrinsic porosity define penetration, retraction, and rebound regimes. On average, at an impact Weber number of ≈80, staggered fibers reduce penetration by 24% in hydrophilic fibers and 34% in hydrophobic fibers, and the penetration reduction percentage is expected to increase with increasing Weber number. Our results indicate that as density grows toward the density of mammalian pelts, penetration will reach a maximum value independent of drop impact velocity, thereby providing an effective rain barrier. Hydrophilicity at the densities we test, 50-150 strands/cm2, aids fiber array resistance to dynamic penetration by impacting drops through the promotion of lateral drop spreading and inhibition of drop fragmentation. Conversely, hydrophobic fibers best resist low-speed wicking. The fraction of a drop that infiltrates hydrophilic and hydrophobic fibers is nearly identical for a fixed Weber number because lateral spreading restricts the penetration depth into hydrophilic fibers but does not restrict mass infiltration. Above a critical Weber number, the entire drop mass penetrates fiber arrays regardless of strand wettability.

Multivariable prognostic modelling to improve prediction of colorectal cancer recurrence: the PROSPeCT trial.

OBJECTIVE: Improving prognostication to direct personalised therapy remains an unmet need. This study prospectively investigated promising CT, genetic, and immunohistochemical markers to improve the prediction of colorectal cancer recurrence. MATERIAL AND METHODS: This multicentre trial (ISRCTN 95037515) recruited patients with primary colorectal cancer undergoing CT staging from 13 hospitals. Follow-up identified cancer recurrence and death. A baseline model for cancer recurrence at 3 years was developed from pre-specified clinicopathological variables (age, sex, tumour-node stage, tumour size, location, extramural venous invasion, and treatment). Then, CT perfusion (blood flow, blood volume, transit time and permeability), genetic (RAS, RAF, and DNA mismatch repair), and immunohistochemical markers of angiogenesis and hypoxia (CD105, vascular endothelial growth factor, glucose transporter protein, and hypoxia-inducible factor) were added to assess whether prediction improved over tumour-node staging alone as the main outcome measure. RESULTS: Three hundred twenty-six of 448 participants formed the final cohort (226 male; mean 66 ± 10 years. 227 (70%) had ≥ T3 stage cancers; 151 (46%) were node-positive; 81 (25%) developed subsequent recurrence. The sensitivity and specificity of staging alone for recurrence were 0.56 [95% CI: 0.44, 0.67] and 0.58 [0.51, 0.64], respectively. The baseline clinicopathologic model improved specificity (0.74 [0.68, 0.79], with equivalent sensitivity of 0.57 [0.45, 0.68] for high vs medium/low-risk participants. The addition of prespecified CT perfusion, genetic, and immunohistochemical markers did not improve prediction over and above the clinicopathologic model (sensitivity, 0.58-0.68; specificity, 0.75-0.76). CONCLUSION: A multivariable clinicopathological model outperformed staging in identifying patients at high risk of recurrence. Promising CT, genetic, and immunohistochemical markers investigated did not further improve prognostication in rigorous prospective evaluation. CLINICAL RELEVANCE STATEMENT: A prognostic model based on clinicopathological variables including age, sex, tumour-node stage, size, location, and extramural venous invasion better identifies colorectal cancer patients at high risk of recurrence for neoadjuvant/adjuvant therapy than stage alone. KEY POINTS: Identification of colorectal cancer patients at high risk of recurrence is an unmet need for treatment personalisation. This model for recurrence, incorporating many patient variables, had higher specificity than staging alone. Continued optimisation of risk stratification schema will help individualise treatment plans and follow-up schedules.

Living in the cracks: Two novel genera of Variosea (Amoebozoa) discovered on an urban sidewalk.

Biological soil crusts represent a rich habitat for diverse and complex eukaryotic microbial communities. A unique but extremely common habitat is the urban sidewalk and its cracks that collect detritus. While these habitats are ubiquitous across the globe, little to no work has been conducted to characterize protists found there. Amoeboid protists are major predators of bacteria and other microbial eukaryotes in these microhabitats and therefore play a substantial ecological role. From sidewalk crack soil crusts, we have isolated three naked amoebae with finely tapered subpseudopodia, and a simple life cycle consisting of a trophic amoeba and a cyst stage. Using a holistic approach including light, electron, and fluorescence microscopy as well as phylogenetics using the ribosomal small subunit rRNA gene and phylogenomics using 230 nuclear genes, we find that these amoeboid organisms fail to match any previously described eukaryote genus. However, we determined the amoebae belong to the amoebozoan lineage Variosea based on phylogenetics. The molecular analyses place our isolates in two novel genera forming a grade at the base of the variosean group Protosteliida. These three novel varioseans among two novel genera and species are herein named "Kanabo kenzan" and "Parakanabo toge."

A Near-Infrared Luminescent Cr(III) N-Heterocyclic Carbene Complex.

Photoluminescent coordination complexes of Cr(III) are of interest as near-infrared spin-flip emitters. Here, we explore the preparation, electrochemistry, and photophysical properties of the first two examples of homoleptic N-heterocyclic carbene complexes of Cr(III), featuring 2,6-bis(imidazolyl)pyridine (ImPyIm) and 2-imidazolylpyridine (ImPy) ligands. The complex [Cr(ImPy)3]3+ displays luminescence at 803 nm on the microsecond time scale (13.7 µs) from a spin-flip doublet excited state, which transient absorption spectroscopy reveals to be populated within several picoseconds following photoexcitation. Conversely, [Cr(ImPyIm)2]3+ is nonemissive and has a ca. 500 ps excited-state lifetime.

Plain language summary of the results from the TALAPRO-2 study: Talazoparib plus enzalutamide versus placebo plus enzalutamide for patients with advanced prostate cancer.

WHAT IS THIS SUMMARY ABOUT?: This summary describes the results from the TALAPRO-2 research study (also known as a clinical trial). The TALAPRO-2 study tested the combination of two medicines called talazoparib plus enzalutamide. This combination of medicines was used as the first treatment for adult patients with metastatic castration-resistant prostate cancer. The combination of talazoparib plus enzalutamide was compared with a placebo plus enzalutamide. WHAT IS METASTATIC CASTRATION-RESISTANT PROSTATE CANCER?: Metastatic castration-resistant prostate cancer is a type of cancer that starts in the prostate and has spread to other parts of the body. Castration-resistant means that the cancer continues to grow even when testosterone levels in the blood are reduced to very low levels. Taking medicines to lower testosterone levels in the blood is a standard treatment for men with advanced prostate cancer. WHAT ARE THE AIMS OF THE TALAPRO-2 TRIAL?: TALAPRO-2 looked at if combining talazoparib plus enzalutamide would increase the length of time patients lived before their cancer got worse or they died compared with a placebo plus enzalutamide. Researchers looked at how treatment affected the size and number of tumors and the length of time before patients needed to change to a new cancer medicine. Researchers also looked at any side effects patients had during the study. WHAT ARE THE KEY TAKEAWAYS?: A total of 805 patients with metastatic castration-resistant prostate cancer took part in the study. Compared with patients who took a placebo plus enzalutamide, the group of patients who took talazoparib plus enzalutamide had a 37% reduced risk of their cancer getting worse or dying. Some patients had tumors that at the start of the study could be measured with scans. Sixty-two percent of patients who took talazoparib plus enzalutamide had their tumors decrease or shrink to the point that they could no longer be seen on scans versus 44% of patients who took a placebo plus enzalutamide. Patients who took talazoparib plus enzalutamide were more likely to have a longer time before they needed to change to a new cancer medicine. The most common side effects of talazoparib plus enzalutamide were low levels of red blood cells (66% of patients) and neutrophils (36% of patients), and excessive tiredness or exhaustion (34% of patients).Clinical Trial Registration: NCT03395197 (TALAPRO-2) (ClinicalTrials.gov).

Assessing asymmetrical kidney function in living donors: a retrospective cohort study on CT metrics.

BACKGROUND: Live donor kidney transplantation is the preferred kidney replacement therapy for eligible patients but requires thorough donor evaluation to minimise risks. Contemporary guidelines recommend split kidney function measurement in living donors only when there is a significant kidney size discrepancy, yet the evidence for this is poor, and practice varies nationally. This study evaluates the efficacy of CT-derived kidney metrics in detecting significant functional asymmetry. METHODS: We conducted a retrospective cohort analysis of 123 prospective living kidney donors at a regional transplant centre from June 2011 to October 2014, utilising CT to determine kidney and cortical volumes and lengths. Asymmetric kidney function (AKF), defined by > 10% function difference on DMSA scans, was correlated with CT measurements to calculate the diagnostic accuracy of current guidelines. RESULTS: Among the prospective donors, the median age was 42 years, and 59.3% were female. The median split kidney function difference was 4%, with 25 individuals exhibiting > 10% AKF. Kidney length discrepancy proved to be a poor indicator of AKF (sensitivity: 28%, specificity: 84%). While negative predictive values for cortical and kidney volumes were high (96% and 93%, respectively), sensitivity was low, and specificity and positive predictive value did not meet satisfactory thresholds. CONCLUSIONS: CT-derived metrics of kidney length, cortical, and total volume show limited sensitivity and specificity in identifying significant AKF. These findings provide evidence to support revised guideline development in the assessment of living kidney donors.

Evaluating barriers to reaching women with public health information in remote communities in Mali.

Telecommunications offers an alternative or supplement to community-based interventions as a means of extending healthcare services and improving health outcomes in remote settings but can fail to reach target communities and achieve the desired impact if barriers to access are not overcome. We conducted seven focus group discussions and 26 interviews with community health workers, community leaders, and female members of the public who declared that they had or had not previously accessed free audio health messages provided via a mobile platform in two rural communities of Mali, Koulikoro and Bougouni. A content analysis showed that participants accessed and trusted health information from a range of sources, including radio, telephone and television, as well as town criers, local relays and community health centres. Barriers to access faced by women included economic factors, lack of network or electricity, and social factors such as illiteracy, cultural restrictions and being unaware of mobile communication. Through analysis and interpretation of the participants' responses, we have made recommendations for future campaigns for the dissemination of health-related information for women in remote settings.

Application of the international system for reporting serous fluid cytopathology on pleural effusion cytology with paired pleural biopsy: A new insight and novel approach on risk of malignancy.

INTRODUCTION: The risk of malignancy (ROM) remains an area of interest for further evaluation in reporting systems including in International System for reporting serous fluid cytopathology (TIS), which is a standardized system for reporting effusion cytology. Herein, we report our findings in further investigation of ROM in TIS by studying on paired pleural effusion specimens and corresponding pleural biopsies with emphasis on negative for malignancy, and atypia of undetermined significance categories. MATERIALS AND METHODS: The  Johns Hopkins Hospital pathology database was retrospectively searched for patients with a pleural biopsy (PBX) and a paired pleural effusion (PF) cytology specimens over a 4-year period. We employed the TIS categories. The following statistical parameters were evaluated: sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV), and ROM. RESULTS: A total of 223 patient cases were included. Effusions TIS reclassification and ROM were as follows: 1.8% non-diagnostic (ROM 75%), 75.8% negative for malignancy (ROM 23%), 4.9% atypical cells of undetermined significance (ROM 45%), 2.2% suspicious for malignancy (ROM 80%), and 15.2% malignant (ROM 100%). Overall accuracy, sensitivity, specificity, PPV and NPV were calculated and were 79.4%, 45%, 97.7%, 91.2% and 77%, respectively. Among, discordant cases diagnosed negative for malignancy on PF and positive for malignancy on PBX, there were significant number of lymphomas, mesotheliomas, and sarcomas. Lung cancer was the most common carcinoma; however, rare types of carcinomas were noted. Cells blocks and immunohistochemistry (IHC) studies were utilized to confirm either malignant conditions or rule out malignancy in both cell blocks and histology biopsies. CONCLUSION: This study demonstrates the high specificity and ROM for 'malignant' and 'suspicious for malignancy' categories in the TIS reporting system and highlights the modest negative predictive value for the 'negative for malignancy' category. Although Tissue biopsies are usually considered as 'gold standard', any definitive diagnosis of malignancy of body fluid should be considered positive for malignancy in further clinical decision-making.

Clinical presentation and magnetic resonance imaging findings of a spinal cord ganglioglioma in a 7.5-year-old, male, neutered German shepherd dog.

A dog presented with a 1-month history of left-sided hemiparesis. MRI showed a focal, 4-cm-long, symmetrical, ovoid, poorly demarcated intramedullary expansion at C6-C7 that was T2-weighted hyperintense, T1-weighted isointense, and noncontrast enhancing. After clinical progression and euthanasia, pathology revealed a neoplasm composed of astrocytes and dysmorphic neurons, consistent with a ganglioglioma. The diagnosis was confirmed with immunohistochemistry and transmission electron microscopy, which demonstrated electron-dense granules in the perikaryon. Gangliogliomas are rare, benign neoplasms that may present as intramedullary spinal cord neoplasia. This is the first report on the clinical presentation, imaging, and pathology of a canine spinal ganglioglioma.

Toxicities of Novel Agents for the Treatment of Advanced Bladder Cancer.

Enfortumab vedotin and erdafitinib have specific toxicities that need careful management in order to optimise drug exposure while maintaining patients' quality of life. Patient education, meticulous monitoring, and a multidisciplinary approach are key to optimising outcomes so that patients can reap the benefits of these new treatments.

Dormancy of a specialist herbivore, Anthonomus rufipennis (Coleoptera: Curculionidae), in a dry tropical forest.

The life history aspects of dormancy of the weevil Anthonomus rufipennis LeConte (Coleoptera: Curculionidae) were studied a 57-month period in a seasonally dry tropical forest of central Mexico. Weevil populations and their physiological status were monitored on both the reproductive host tree, Senna polyantha (Collad.) H.S: Irwin & Barneby (Fabales: Fabaceae) and the highly favored refuge host, Tillandsia recurvata L. (Poales: Bromeliaceae) or "ball moss." During the dry season, weevils were only found on the refuge host with a mean total density of 1.014 ± 2.532 individuals/ball moss (N = 1,681). Weevil densities on T. recurvata between early and late dry seasons were not significantly different, suggesting that dry season survival was relatively high. Weevils collected during these seasons revealed little reproductive development and relatively high-fat accumulation in both sexes. During 5 of 6 yr, densities of the weevils in T. recurvata dropped significantly during the early rainy seasons, when the reproductive host trees leafed out and began producing oviposition sites (flower buds). At this time, more males than females initially moved to vegetative trees and showed significant signs of reproductive development. Recolonization of ball moss by weevils began during the late rainy season when oviposition sites (flower buds) were still available. A proportion of the weevils remained on the reproductive host, suggesting that A. rufipennis is facultatively multivoltine. The methodologies and results of the study can serve as a model system for future studies of the dormancy of other insects in dry tropical forests and provide insight into the dormancy of other anthonomine weevils of economic importance.

Turmeric-induced Liver Injury.

The use of herbal and dietary supplements has gained an increasing foothold in the United States. While often touted as safer alternatives to more traditional "western" therapeutics, the pharmacology and pharmacokinetics of these substances, their interactions with other medications, their purity, and individual pharmacogenomics, remain unknown. Turmeric is a popular supplement that has been demonstrated to be safe, and even hepatoprotective. Recently, however, there have been several reports of turmeric-induced liver injury. We report a case of drug-induced liver injury due to turmeric that was complicated by acute liver failure and hepatorenal syndrome.

Implications of bone metastasis on response to systemic therapy in patients with advanced renal cell carcinoma: A systematic literature review.

INTRODUCTION: Bone metastases negatively affect prognosis in patients with advanced renal cell carcinoma (aRCC). We conducted a systematic literature review to identify clinical trial publications including patients with aRCC with and without bone metastases. METHODS: The review was conducted according to Preferred Reporting Items for Systematic Reviews and Meta­Analyses (PRISMA) guidelines and registered with PROSPERO (CRD42022355436). MEDLINE and Embase databases were searched (September 2, 2022) to identify publications reporting efficacy and safety outcomes for patients with/without bone metastasis from clinical trials of systemic RCC therapies. Risk of bias was assessed using Grading of Recommendations Assessment, Development and Evaluation (GRADE). RESULTS: Of 526 publications screened, 19 were eligible: seven (from five studies) reported phase 3 trials, six reported phase 2 trials, one reported phase 1b/2 trials, and five were pooled analyses. Five publications reported moderate-quality evidence, while 14 were graded as low- or very low-quality evidence, suggesting a high potential for uncertainty. Five studies reported benefits of investigational therapies versus comparators in patients with and without bone metastases; these studies included cabozantinib, nivolumab, cabozantinib plus nivolumab, and lenvatinib plus pembrolizumab treatment arms. Data were also available for nivolumab plus ipilimumab. Bone metastases were consistently associated with poor prognosis in patients with aRCC. Preliminary data support the hypothesis that therapies targeting pathways implicated in the development of bone metastases may be beneficial, and warrant further investigation. However, data to support treatment decision-making are lacking. CONCLUSION: Our findings highlight the need for clinical data to assist in defining the optimal treatment for patients with aRCC and bone metastasis.