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Samuraciclib is a selective oral CDK7-inhibitor. A multi-modular, open-label Phase I study to evaluate safety and tolerability of samuraciclib in patients with advanced malignancies was designed (ClinicalTrials.gov: NCT03363893). Here we report results from dose escalation and 2 expansion cohorts: Module 1A dose escalation with paired biopsy cohort in advanced solid tumor patients, Module 1B-1 triple negative breast cancer (TNBC) monotherapy expansion, and Module 2A fulvestrant combination in HR+/HER2− breast cancer patients post-CDK4/6-inhibitor. Core study primary endpoints are safety and tolerability, and secondary endpoints are pharmacokinetics (PK), pharmacodynamic (PD) activity, and anti-tumor activity. Common adverse events are low grade nausea, vomiting, and diarrhea. Maximum tolerated dose is 360 mg once daily. PK demonstrates dose proportionality (120 mg-480 mg), a half-life of approximately 75 hours, and no fulvestrant interaction. In dose escalation, one partial response (PR) is identified with disease control rate of 53% (19/36) and reduction of phosphorylated RNA polymerase II, a substrate of CDK7, in circulating lymphocytes and tumor tissue. In TNBC expansion, one PR (duration 337 days) and clinical benefit rate at 24 weeks (CBR) of 20.0% (4/20) is achieved. In combination with fulvestrant, 3 patients achieve PR with CBR 36.0% (9/25); in patients without detectable TP53-mutation CBR is 47.4% (9/19). In this study, samuraciclib exhibits tolerable safety and PK is supportive of once-daily oral administration. Clinical activity in TNBC and HR+/HER2-breast cancer post-CDK4/6-inhibitor settings warrants further evaluation. Pre-clinical studies have demonstrated the anti-tumor activity of selective inhibitors of CDK7, including samuraciclib. Here the authors report the results from dose escalation and two expansion cohorts in patients with breast cancer of a multi-modular Phase I clinical trial of samuraciclib as anti-cancer treatment. [ABSTRACT FROM AUTHOR]

Background: The Neoadjuvant Breast Symphony Trial (NBRST) demonstrated the 70-gene risk of distant recurrence signature, MammaPrint, and the 80-gene molecular subtyping signature, BluePrint, precisely determined preoperative pathological complete response (pCR) in breast cancer patients. We report 5-year follow-up results in addition to an exploratory analysis by age and menopausal status. Methods: The observational, prospective NBRST (NCT01479101) included 954 early-stage breast cancer patients aged 18–90 years who received neoadjuvant chemotherapy and had clinical and genomic data available. Chemosensitivity and 5-year distant metastasis-free survival (DMFS) and overall survival (OS) were assessed. In a post hoc subanalysis, results were stratified by age (≤ 50 vs. > 50 years) and menopausal status in patients with hormone receptor-positive/human epidermal growth factor receptor 2-negative (HR+/HER2−) tumors. Results: MammaPrint and BluePrint further classified 23% of tumors to a different subtype compared with immunohistochemistry, with more precise correspondence to pCR rates. Five-year DMFS and OS were highest in MammaPrint Low Risk, Luminal A-type and HER2-type tumors, and lowest in MammaPrint High Risk, Luminal B-type and Basal-type tumors. There was no significant difference in chemosensitivity between younger and older patients with Low-Risk (2.2% vs. 3.8%; p = 0.64) or High-Risk tumors (14.5% vs. 11.5%; p = 0.42), or within each BluePrint subtype; this was similar when stratifying by menopausal status. The 5-year outcomes were comparable by age or menopausal status for each molecular subtype. Conclusion: Intrinsic preoperative chemosensitivity and long-term outcomes were precisely determined by BluePrint and MammaPrint regardless of patient age, supporting the utility of these assays to inform treatment and surgical decisions in early-stage breast cancer. [ABSTRACT FROM AUTHOR]

Correction to: I Nature Communications i https://doi.org/10.1038/s41467-023-40061-y, published online 24 July 2023 In this article the author name R. C. Coombes was incorrectly written as R. Charles Coombes. The original article can be found online at https://doi.org/10.1038/s41467-023-40061-y. [Extracted from the article]

Purpose: The Janus-associated kinase (JAK)/signal transducer and activator of transcription pathway is a key regulator of inflammatory signaling, associated with tumorigenesis, cell survival, and progression. This randomized phase 2 trial evaluated the efficacy and safety of the addition of ruxolitinib, a JAK1/JAK2 inhibitor, to capecitabine in patients with HER2-negative advanced breast cancer and high systemic inflammation (modified Glasgow Prognostic Score [mGPS] ≥ 1).Methods: Patients with ≤ 2 prior chemotherapy regimens for advanced or metastatic disease or hormone receptor-positive patients with disease progression on prior hormonal therapies were randomized 1:1 to 21-day cycles of ruxolitinib (n = 76) or placebo (n = 73) plus capecitabine. The primary endpoint was overall survival (OS).Results: Baseline characteristics were well balanced between groups. For ruxolitinib plus capecitabine versus placebo plus capecitabine, median OS was 11.2 months versus 10.9 months (log-rank test P = 0.762); median progression-free survival (PFS) was 4.5 months versus 2.5 months (log-rank test P = 0.151); and overall response rate (ORR) was 28.9% versus 13.7% (Cochran-Mantel-Haenszel test P = 0.024), respectively. A more favorable change in health-related quality of life (HRQoL) was observed with ruxolitinib plus capecitabine versus placebo plus capecitabine. Both regimens were generally tolerable. A higher incidence of grade 3/4 anemia (25.4% vs 5.6%) and a lower incidence of grade 3/4 palmar-plantar erythrodysesthesia (1.4% vs 12.7%) occurred with ruxolitinib plus capecitabine versus placebo plus capecitabine.Conclusions: The addition of ruxolitinib to capecitabine for patients with advanced breast cancer and high systemic inflammation was generally tolerable; ORR was numerically greater, a more favorable change in HRQoL was observed, but neither OS nor PFS was improved compared with placebo plus capecitabine. [ABSTRACT FROM AUTHOR]

Purpose: The phase 3 MONALEESA-2 study demonstrated that addition of ribociclib (RIB) to letrozole (LET) significantly improved progression-free survival (PFS) in patients (pts) with hormone receptor-positive (HR+), HER2-negative (HER2−) advanced breast cancer (ABC). Here, we evaluated duration of response (DoR), tumor shrinkage, PFS by treatment-free interval (TFI), and health-related quality of life (HRQoL).Methods: Postmenopausal women (N = 668) with HR+ , HER2− ABC and no prior systemic therapy for ABC were randomized to RIB (600 mg/day; 3 weeks on/1 week off) plus LET (2.5 mg/day; continuous) or placebo (PBO) plus LET. Primary end point was PFS; HRQoL was the secondary end point; DoR was exploratory end point and PFS by TFI was post hoc analysis.Results: Of 501 pts with measurable disease and confirmed complete or partial response, median DoR was 26.7 months (95% CI, 24.0-NR) in the RIB arm versus 18.6 months (95% CI, 14.8-23.1) in the PBO arm. At 8 weeks, more pts in the RIB arm (32%) versus the PBO arm (17%) experienced best percentage change ≥ 60%. The average pain reduction was greater in the RIB arm (26%) versus the PBO arm (15%). PFS benefit was seen with RIB vs PBO, irrespective of TFI.Conclusion: RIB plus LET versus PBO plus LET is associated with earlier and more durable tumor response, greater degree of tumor shrinkage and pain reduction, and PFS benefit irrespective of TFI. These data further support RIB plus LET as a first-line treatment option for postmenopausal women with HR+ , HER2− ABC. [ABSTRACT FROM AUTHOR]

Background: Pertuzumab became a standard part of neoadjuvant therapy for human epidermal growth factor receptor 2-positive (HER2+) breast cancers approximately halfway through Neoadjuvant Breast Registry Symphony Trial (NBRST) enrollment, providing a unique opportunity to determine biologically which clinical HER2+ patients benefit most from dual targeting. As a neoadjuvant phase 4 study, NBRST classifies patients by both conventional and molecular subtyping. Methods: Of 308 clinical HER2+ patients enrolled in NBRST between 2011 and 2014 from 62 U.S. institutions, 297 received neoadjuvant chemotherapy (NCT) with HER2-targeted therapy and underwent surgery. This study compared the pathologic complete response (pCR) rate of BluePrint versus clinical subtypes with treatment, specifically differences between trastuzumab (T) treatment and trastuzumab and pertuzumab (T/P) treatment. Results: In this study, 60% of the patients received NCT-T, and 40% received NCT-T/P. The overall pCR rate (ypT0/isN0) was 47%. BluePrint classified 161 tumors (54%) as HER2 type, with a pCR rate of 65%. This was significantly higher than the pCR rate for the 91 HER2+ tumors (31%) classified as luminal (18%) ( p = 0.00001) and the 45 tumors (15%) classified as basal (44%) ( p = 0.0166). The patients treated with T/P had higher pCR rates than those treated with trastuzumab alone. The difference was most pronounced in the BluePrint luminal patients (8 vs. 31%). The highest pCR was reached by the BluePrint HER2-type patients treated with T/P (76%). Conclusions: The addition of pertuzumab leads to increased pCR rates for all HER2+ patient groups except for the BluePrint basal-type patients. This better response was most pronounced for the BluePrint luminal-type patients. [ABSTRACT FROM AUTHOR]

Background: The prospective Neoadjuvant Breast Symphony Trial (NBRST) study found that MammaPrint/BluePrint functional molecular subtype is superior to conventional immunohistochemistry/fluorescence in situ hybridization subtyping for predicting pathologic complete response (pCR) to neoadjuvant chemotherapy. The purpose of this substudy was to determine if the rate of pCR is affected by tumor size. Methods: The NBRST study includes breast cancer patients who received neoadjuvant chemotherapy. MammaPrint/BluePrint subtyping classified patients into four molecular subgroups: Luminal A, Luminal B, HER2 (human epidermal growth factor receptor 2), and Basal type. Probability of pCR (ypT0/isN0) as a function of tumor size and molecular subgroup was evaluated. Results: A total of 608 patients were evaluable with overall pCR rates of 28.5 %. Luminal A and B patients had significantly lower rates of pCR (6.1 and 8.7 %, respectively) than either basal (37.1 %) or HER2 (55.0 %) patients ( p < 0.001). The probability of pCR significantly decreased with tumor size >5 cm [ p = 0.022, odds ratio (OR) 0.58, 95 % confidence interval (CI) 0.36, 0.93]. This relationship was statistically significant in the Basal ( p = 0.026, OR 0.46, 95 % CI 0.23, 0.91) and HER2 ( p = 0.039, OR 0.36, 95 % CI 0.14, 0.95) subgroups. In multivariate logistic regression analyses, the dichotomized tumor size variable was not significant in any of the molecular subgroups. Discussion: Even though tumor size would intuitively be a clinical determinant of pCR, the current analysis showed that the adjusted OR for tumor size was not statistically significant in any of the molecular subgroups. Factors significantly associated with pCR were PR status, grade, lymph node status, and BluePrint molecular subtyping, which had the strongest correlation. [ABSTRACT FROM AUTHOR]

Trabectedin is an alkylating agent that binds to the minor groove of DNA. Early studies with trabectedin suggested efficacy in triple-negative and HER2-overexpressing metastatic breast cancer (MBC). The efficacy and safety of trabectedin in pretreated patients with these tumors were evaluated in this parallel-cohort phase II trial. Patients received a 3-h infusion of trabectedin 1.3 mg/m intravenously every 3 weeks until progression or unmanageable/unacceptable toxicity. The primary objective was to evaluate the efficacy using the objective response rate (ORR) as per Response Evaluation Criteria In Solid Tumors (RECIST). Secondary objectives comprised time-to-event endpoints and safety assessed with the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE) v.3.0. Patients with heavily pretreated triple-negative ( n = 50) or HER2-overexpressing ( n = 37) MBC were enrolled. No confirmed responses were found in triple-negative MBC patients, with median progression-free survival (PFS) of 2.2 months (95 % CI 1.3-2.7 months). Confirmed partial responses occurred in 4 of 34 evaluable HER2-overexpressing MBC patients (ORR = 12 %; 95 % CI 3-27 %) and lasted a median of 12.5 months (95 % CI, 6.2-14.7 months); median PFS was 3.8 months (95 % CI, 1.8-5.5 months). Most trabectedin-related adverse events were mild or moderate, and the most frequent were fatigue, nausea, vomiting, constipation, and anorexia. Severe neutropenia and transaminase increases were non-cumulative and transient and were mostly managed by infusion delays or dose reductions. Single-agent trabectedin is well tolerated in aggressive MBC and has moderate activity in HER2-overexpressing tumors. Further studies are warranted to evaluate trabectedin combined with HER2-targeted treatments in this subtype. [ABSTRACT FROM AUTHOR]

The ever expanding role of a forensic neuropsychologist in civil litigation has rightfully led to a higher level of expectation for this expert, in realms such as clinical and courtroom knowledge, objectivity, and work product utility. The onus is on forensic neuropsychologists to ensure that these expectations are met. Recognizing that bias is inherent in clinical and forensic work, it is imperative that in high stakes situations such as forensic neuropsychological assessment, the evaluator is proactively conscientious in recognizing, and minimizing, the effects of these biases. This article highlights 12, of many, common biases about which the prudent forensic neuropsychologist should always be mindful of, during evaluation as well as the provision of deposition or trial testimony. Role, cognitive, and practice biases are defined and illustrated with examples. Specific suggestions are extracted from both empirical literature and forensic experience on how to recognize and mitigate these biases. The information contained in this article is intended to provide sound and practical strategies that can be useful for forensic neuropsychological practitioners. Attorneys will also find the content useful when working with such experts, including during deposition and cross examination preparation. [ABSTRACT FROM AUTHOR]

Purpose: The purpose of the NBRST study is to compare a multigene classifier to conventional immunohistochemistry (IHC)/fluorescence in situ hybridization (FISH) subtyping to predict chemosensitivity as defined by pathological complete response (pCR) or endocrine sensitivity as defined by partial response. Methods: The study includes women with histologically proven breast cancer, who will receive neoadjuvant chemotherapy (NCT) or neoadjuvant endocrine therapy. BluePrint in combination with MammaPrint classifies patients into four molecular subgroups: Luminal A, Luminal B, HER2, and Basal. Results: A total of 426 patients had definitive surgery. Thirty-seven of 211 (18 %) IHC/FISH hormone receptor (HR)+/HER2− patients were reclassified by Blueprint as Basal ( n = 35) or HER2 ( n = 2). Fifty-three of 123 (43 %) IHC/FISH HER2+ patients were reclassified as Luminal ( n = 36) or Basal ( n = 17). Four of 92 (4 %) IHC/FISH triple-negative (TN) patients were reclassified as Luminal ( n = 2) or HER2 ( n = 2). NCT pCR rates were 2 % in Luminal A and 7 % Luminal B patients versus 10 % pCR in IHC/FISH HR+/HER2− patients. The NCT pCR rate was 53 % in BluePrint HER2 patients. This is significantly superior ( p = 0.047) to the pCR rate in IHC/FISH HER2+ patients (38 %). The pCR rate of 36 of 75 IHC/FISH HER2+/HR+ patients reclassified as BPLuminal is 3 %. NCT pCR for BluePrint Basal patients was 49 of 140 (35 %), comparable to the 34 of 92 pCR rate (37 %) in IHC/FISH TN patients. Conclusions: BluePrint molecular subtyping reclassifies 22 % (94/426) of tumors, reassigning more responsive patients to the HER2 and Basal categories while reassigning less responsive patients to the Luminal category. These findings suggest that compared with IHC/FISH, BluePrint more accurately identifies patients likely to respond (or not respond) to NCT. [ABSTRACT FROM AUTHOR]

The niche of forensic neuropsychology and use of neuropsychologists as expert witnesses has proliferated over the past two decades. Neuropsychologists conduct evaluations or provide consultation to assist triers of fact in both civil and criminal arenas. This article delivers a succinct overview of an array of factors that warrant consideration from the time of referral for a neuropsychological evaluation through the delivery of a verdict or settlement and receipt of payment for services. Readers are offered a primer on relevant legal criteria, distinctions between court settings, and applicable ethical standards and guidelines. Suggestions are made regarding the expert witness retention agreement and strategies for direct and cross examination are reviewed. Logistical and liability considerations are also explored. Real world examples are included to illustrate some of the obstacles that neuropsychologist expert witnesses may encounter. [ABSTRACT FROM AUTHOR]

Lapatinib, an oral, reversible inhibitor of epidermal growth factor receptor and human epidermal growth factor receptor 2 (HER2) tyrosine kinase, has proven antitumor activity in HER2-positive metastatic breast cancer (MBC). Nanoparticle albumin-bound paclitaxel ( nab-paclitaxel) is indicated for the treatment of breast cancer after failure of combination chemotherapy for metastatic disease or relapse within 6 months of adjuvant chemotherapy. This was an open-label, single-arm, multicenter, Phase II study to evaluate the efficacy and safety of nab-paclitaxel plus lapatinib in women with HER2 over-expressing MBC who had received no more than one prior chemotherapeutic regimen. The primary efficacy endpoint was the overall response rate (ORR). This was defined as the percentage of patients having either a complete response (CR) or partial response (PR). Secondary efficacy endpoints included progression-free survival (PFS), overall survival, duration of response (DoR), time to response (TTR), and time to progression (TTP). Investigator-assessed ORR was 53 % ( n = 32, 95 % confidence interval (CI): 40.7-66.0) with the majority of patient responses demonstrating a PR (47 %). Four (7 %) patient responses demonstrated a CR, and ten (17 %) a stable disease. The median Kaplan-Meier estimate of investigator-assessed PFS, DoR, TTR, and TTP was 39.7 weeks (95 % CI 34.1-63.9), 48.7 weeks (95 % CI 31.7-57.1), 7.8 weeks (95 % CI 7.4-8.1), and 41 weeks (95 % CI 39.1-64.6), respectively. Lapatinib 1,000 mg with nab-paclitaxel 100 mg/m IV is feasible with manageable and predictable toxicity and an ORR of 53 % comparing favorably with other HER2-based combinations in this setting. [ABSTRACT FROM AUTHOR]

Rice breeding and crop research predominantly emphasize adaptation to ecological conditions. Based on qualitative and quantitative research conducted between 2000 and 2012 we show how ecological factors, combined with socioeconomic variables, cultural norms and values, shape the use and development of local technologies related to the cultivation of African rice ( Oryza glaberrima Steud.) in seven West African countries (Ghana, Guinea, Guinea-Bissau, Senegal, Sierra Leone, The Gambia and Togo). In this region the role of African rice is diverse across ethnic groups. Findings suggest that farmers, through various pathways, are active in the development of promising new varieties based on genetic resources of Asian rice, African rice, or both, as well as in the adoption of modern varieties. These findings require further research into interactions among ecological, genetic, socioeconomic and cultural factors within farmers' innovation systems and recognition of emergent knowledge and technologies resulting from such interactions. [ABSTRACT FROM AUTHOR]

It is widely recognized that mineral fertilizers must play an important part in improving agricultural productivity in western Kenyan farming systems. This paper suggests that for this goal to be realized, farmers’ knowledge must be strengthened to improve their understanding of fertilizers and their use. We analyzed smallholder knowledge of fertilizers and nutrient management, and draw practical lessons from empirical collective fertilizer- response experiments. Data were gathered from the collective fertilizer-response trials, through focus group discussions, by participant observation, and via in-depth interviews representing 40 households. The collective trials showed that the application of nitrogen (N) or phosphorous (P) alone was insufficient to enhance yields in the study area. The response to P on the trial plots was mainly influenced by incidences of the parasitic Striga weed, by spatial variability or gradients in soil fertility of the experimental plots, and by interactions with N levels. These results inspired farmer to design and conduct experiments to compare crop performance with and without fertilizer, and between types of fertilizers, or responses on different soils. Participating farmers were able to differentiate types of fertilizer, and understood rates of application and the roles of respective fertilizers in nutrient supply. However, notions were broadly generated by unsteady yield responses when fertilizers were used across different fertility gradients, association with high cost (especially if recommended rates were to be applied), association of fertilizer use with hybrids and certain crops, historical factors, among other main aspects. We identified that strengthening fertilizer knowledge must be tailored within existing, albeit imperfect, systems of crop and animal husbandry. Farmers’ perceptions cannot be changed by promoting more fertilizer use alone, but may require a more basic approach that, for example, encourages farmer experimentation and practices to enhance soil properties such as carbon build-up in impoverished local soils. [ABSTRACT FROM AUTHOR]

Traumatic brain injuries (TBIs) are prevalent across the lifespan and occur from multiple sources (e.g., motor vehicle accidents, falls, sports injuries, assaults, abuse). Because many of these injuries are compensable, plaintiff and defense counsel often rely on the expertise of a forensic neuropsychologist to help establish or refute the claim of the presence of TBI, or the degree of severity claimed. In this paper, we offer a tutorial in which we provide information that attorneys need to know in handling of TBI cases: We address definitions, epidemiology, pathophysiology, guidelines for grading TBI severity, and treatment. Also, we cover moderating variables that affect TBI outcome and recovery and specific forensic issues that may arise in the neuropsychological evaluation (e.g., symptom magnification, malingering). Although the focus is on mild TBI in adults, we also cover the more serious variants of moderate and severe adult TBI and include a separate all-severity section on pediatric populations. We consider the special challenges the attorney faces, for example, in establishing causality. [ABSTRACT FROM AUTHOR]

We compare traditional methods of seismic event location, based on phase pick data and analysis of events one-at-a-time, with a modern method based on cross-correlation measurements and joint analysis of numerous events. In application to four different regions representing different types of seismicity and monitored with networks of different station density, we present preliminary results indicating what fraction of seismic events may be amenable to analysis with modern methods. The latter can supply locations ten to a hundred times more precise than traditional methods. Since good locations of seismic sources are needed as the starting point for so many user communities, and potentially can be provided due to current improvements in easily-accessible computational capability, we advocate wide-scale application of modern methods in the routine production of bulletins of seismicity. This effort requires access to waveform archives from well-calibrated stations that have long operated at the same location. [ABSTRACT FROM AUTHOR]

Reports findings which suggest that the annual rotation of the Earth's inner core is faster than the daily rotation of the mantle and crust. Study of three decades of seismic data; The small but systematic variation of travel times of the seismic waves in the inner core; Implications of these detectable inner-core motions.

Following the nuclear test carried out by North Korea on 9 October 2006, seismic data provided a detailed picture of the event — negating arguments against the Comprehensive Nuclear Test Ban Treaty based on allegations of inadequate monitoring capability. [ABSTRACT FROM AUTHOR]

Reports on a recent testing of mechanisms used to monitor international compliance to the Comprehensive Test Ban treaty. Study of an earthquake off the coast of Novaya Zemlya, an island to north of the Russian mainland; Unresolved questions as to whether the cause was natural or if it was an underground nuclear test; Details of how the monitoring system worked; Implications.

Presents views on the nuclear testing monitoring. Disagreement on verification capability; Detection and location of explosions using seismological methods; Differentiation from earthquakes; Hope for global monitoring; Technical tests by the subcommittee of the United Nations in Geneva, known as the Group of Scientific Experts. INSET: Call for extended moratorium, by Paul G. Richards..

Presents an obituary to the late Keiiti Aki who died on May 17, 2005.

With increased upstream withdrawal of Ganga waters for irrigation and urban industrial uses, Ganga's dry season flow is declining. The heavily populated but marginalised north Indian State of Bihar with itscapital at Patna expects the Union government in Delhi to curb the appetite of upstream States; but Delhi's water bureaucracy, having grown within a culture of 'construction' rather than 'water management',is reluctant to do so. Adding to Patna's anxiety is a new fear in the form of the 1996 Farakka Treaty between India and Bangladesh, an international obligation that Patna fears will further curtail its water rights. Delhi, however, is able to placate Patna with promises of aKosi High Dam in Nepal on the major tributary of the Ganga closest to Bihar. Because both bureaucracies belong to a social solidarity of hierarchic procedures that would make similar technological choices, Patna is pacified. On the other hand, activist groups in Bihar belonging to a different solidarity, that of egalitarian equity, point to the dismal consequences of past technological choices (embankments) onthe land and its poor and continue to oppose this new choice as well. The hierarchic discourse between Patna and Delhi, however, filters out this activist critique and pursues a business-as-usual program ofnew high dam construction. The purpose of this paper is to examine the institutional background behind such rigid, single-mission policies and the costly surprises and impasse they are prone to. The paper argues that sagaciously providing space for constructive engagement among differing perspectives of the state, market and civil society on Bihar's water problems may minimize this risk. [ABSTRACT FROM AUTHOR]