Promising Directions: A Systematic Review of Psychosocial and Behavioral Interventions with Cultural Incorporation for Advanced and Metastatic Cancer.

BACKGROUND: Improving quality of life (QOL) in advanced and metastatic cancer is a priority with increasing survivorship. This systematic review synthesizes psychosocial and behavioral interventions incorporating culture with the goal of examining their benefit for understudied and medically underserved populations with advanced and metastatic cancer. METHOD: Reports were systematically screened for (1) a focus on advanced and metastatic cancer survivors, (2) psychosocial or behavioral intervention intended to improve QOL, (3) evidence of incorporating the culture(s) of understudied/underserved populations, and (4) availability in English. Bias was evaluated using the JBI Critical Appraisal Checklist and the Methodological index for non-randomized studies. Qualitative synthesis and quantitative meta-analyses were completed. RESULTS: Eighty-six reports containing 5981 participants' data were examined. Qualitative synthesis of 23 studies identified four overarching themes relevant for incorporating culture in interventions. Meta-analysis of 19 RCTs and 4 quasi-experimental studies containing considerable heterogeneity indicated greater improvements in QOL (g = 0.84), eudaimonic well-being (g = 0.53), distress (g = -0.49), and anxiety (g = -0.37) for main intervention conditions compared to controls. Meta-analysis of 10 single-arm trials containing minimal to moderate heterogeneity found benefit for anxiety (g = -0.54), physical symptoms (g = -0.39), and depression (g = -0.38). CONCLUSION: Psychosocial and behavioral interventions with cultural incorporation appear beneficial for improving QOL-related outcomes in advanced and metastatic cancer. Studies incorporating culture in psychosocial or behavioral interventions offer noteworthy insight and suggestions for future efforts such as attending to deep cultural structure.

The history and evolution of the Denisovan-EPAS1 haplotype in Tibetans.

Recent studies suggest that admixture with archaic hominins played an important role in facilitating biological adaptations to new environments. For example, interbreeding with Denisovans facilitated the adaptation to high-altitude environments on the Tibetan Plateau. Specifically, the EPAS1 gene, a transcription factor that regulates the response to hypoxia, exhibits strong signatures of both positive selection and introgression from Denisovans in Tibetan individuals. Interestingly, despite being geographically closer to the Denisova Cave, East Asian populations do not harbor as much Denisovan ancestry as populations from Melanesia. Recently, two studies have suggested two independent waves of Denisovan admixture into East Asians, one of which is shared with South Asians and Oceanians. Here, we leverage data from EPAS1 in 78 Tibetan individuals to interrogate which of these two introgression events introduced the EPAS1 beneficial sequence into the ancestral population of Tibetans, and we use the distribution of introgressed segment lengths at this locus to infer the timing of the introgression and selection event. We find that the introgression event unique to East Asians most likely introduced the beneficial haplotype into the ancestral population of Tibetans around 48,700 (16,000-59,500) y ago, and selection started around 9,000 (2,500-42,000) y ago. Our estimates suggest that one of the most convincing examples of adaptive introgression is in fact selection acting on standing archaic variation.

Use of a digital contact tracing system in Singapore to mitigate COVID-19 spread.

BACKGROUND: Contact tracing has been essential to reducing spread of COVID-19. Singapore leveraged technology to assist with contact tracing efforts using a Bluetooth-based app and token platform called 'TraceTogether'. METHODS: We reviewed the impact of this system during the country's Delta and Omicron waves (24 August 2021 to 17 February 2022) to identify differences in number of close contacts and time savings between full automation using TraceTogether alone as compared to manual contact tracing supplemented by TraceTogether. Characteristics of digital contact tracing app or token users were reviewed. Thereafter, the number of close contacts identified by manual and digital contact tracing methods, and the number of confirmed COVID-19 cases among contacts were analysed. The difference in time taken for identification of close contacts was also determined. FINDINGS: Adoption rate for TraceTogether was high, with 93.3% of cases having a registered device. There was a 9.8 h (34.9%) reduction in time savings for close contacts to be informed using TraceTogether alone compared to manual contact tracing supplemented by TraceTogether. The proportion of close contacts automatically identified through TraceTogether alone and turned positive was 3.6%. For those identified through manual contact tracing supplemented by TraceTogether, this proportion was 12.5% and 6.2% for those served quarantine orders and health risk warnings respectively. INTERPRETATION: The high adoption rate of 'TraceTogether' suggest that digital solutions remain a promising option to improve contact tracing in future epidemics. This may have been through its concurrent use with vaccine differentiated public health measures and policies which engender public trust. There is future potential for utilising such technology in managing communicable diseases to achieve good public health outcomes.

Defining the requirements for the pathogenic interaction between mutant calreticulin and MPL in MPN.

Mutations in calreticulin (CALR) are phenotypic drivers in the pathogenesis of myeloproliferative neoplasms. Mechanistic studies have demonstrated that mutant CALR binds to the thrombopoietin receptor MPL, and that the positive electrostatic charge of the mutant CALR C terminus is required for mutant CALR-mediated activation of JAK-STAT signaling. Here we demonstrate that although binding between mutant CALR and MPL is required for mutant CALR to transform hematopoietic cells; binding alone is insufficient for cytokine independent growth. We further show that the threshold of positive charge in the mutant CALR C terminus influences both binding of mutant CALR to MPL and activation of MPL signaling. We find that mutant CALR binds to the extracellular domain of MPL and that 3 tyrosine residues within the intracellular domain of MPL are required to activate signaling. With respect to mutant CALR function, we show that its lectin-dependent function is required for binding to MPL and for cytokine independent growth, whereas its chaperone and polypeptide-binding functionalities are dispensable. Together, our findings provide additional insights into the mechanism of the pathogenic mutant CALR-MPL interaction in myeloproliferative neoplasms.

Composite likelihood method for inferring local pedigrees.

Pedigrees contain information about the genealogical relationships among individuals and are of fundamental importance in many areas of genetic studies. However, pedigrees are often unknown and must be inferred from genetic data. Despite the importance of pedigree inference, existing methods are limited to inferring only close relationships or analyzing a small number of individuals or loci. We present a simulated annealing method for estimating pedigrees in large samples of otherwise seemingly unrelated individuals using genome-wide SNP data. The method supports complex pedigree structures such as polygamous families, multi-generational families, and pedigrees in which many of the member individuals are missing. Computational speed is greatly enhanced by the use of a composite likelihood function which approximates the full likelihood. We validate our method on simulated data and show that it can infer distant relatives more accurately than existing methods. Furthermore, we illustrate the utility of the method on a sample of Greenlandic Inuit.

Association between depth of response and survival in patients with advanced-stage non-small cell lung cancer treated with first-line chemotherapy.

BACKGROUND: A partial response according to the Response Evaluation Criteria in Solid Tumors includes a wide range of changes in tumor size. This study evaluated whether further specification of tumor reduction based on the depth of response (DpR) would provide a more precise association with outcomes for patients with non-small cell lung cancer (NSCLC) treated with first-line platinum-based chemotherapy. METHODS: A retrospective analysis was performed for the randomized phase 3 CA031 trial in patients with NSCLC treated with carboplatin in combination with nab-paclitaxel or solvent-based paclitaxel. Quartiles according to the maximum tumor reduction from the baseline were defined (quartile 1 [Q1], >0% to 25%; quartile 2 [Q2], >25% to 50%; quartile 3 [Q3], >50% to 75%; and quartile 4 [Q4], >75%) and were compared with those patients with no tumor reduction (NTR). The primary objective was to evaluate the association between DpR and overall survival (OS). RESULTS: Of the 1052 patients enrolled in the CA031 trial, 959 (91%) were evaluable, and they included 365 (38.1%) who were classified as Q1, 327 (34.1%) who were classified as Q2, 131 (13.7%) who were classified as Q3, and 34 (3.5%) who were classified as Q4; 102 had NTR (10.6%). The median OS values for patients in the NTR, Q1, Q2, Q3, and Q4 groups were 4.8, 10.4, 14.5, 19.3, and 23.5 months, respectively. The maximum DpR on treatment was an independent predictor of improved OS in comparison with patients with NTR; the hazard ratio decreased from 0.43 in Q1 to 0.16 in Q4. CONCLUSIONS: DpR was strongly associated with OS in patients with NSCLC receiving first-line platinum-based therapy. Additional studies may help to define the role of DpR in solid tumors.

Archaic Adaptive Introgression in TBX15/WARS2.

A recent study conducted the first genome-wide scan for selection in Inuit from Greenland using single nucleotide polymorphism chip data. Here, we report that selection in the region with the second most extreme signal of positive selection in Greenlandic Inuit favored a deeply divergent haplotype that is closely related to the sequence in the Denisovan genome, and was likely introgressed from an archaic population. The region contains two genes, WARS2 and TBX15, and has previously been associated with adipose tissue differentiation and body-fat distribution in humans. We show that the adaptively introgressed allele has been under selection in a much larger geographic region than just Greenland. Furthermore, it is associated with changes in expression of WARS2 and TBX15 in multiple tissues including the adrenal gland and subcutaneous adipose tissue, and with regional DNA methylation changes in TBX15.

Dynamin 2-dependent endocytosis is required for normal megakaryocyte development in mice.

Dynamins are highly conserved large GTPases (enzymes that hydrolyze guanosine triphosphate) involved in endocytosis and vesicle transport, and mutations in the ubiquitous and housekeeping dynamin 2 (DNM2) have been associated with thrombocytopenia in humans. To determine the role of DNM2 in thrombopoiesis, we generated Dnm2(fl/fl) Pf4-Cre mice specifically lacking DNM2 in the megakaryocyte (MK) lineage. Dnm2(fl/fl) Pf4-Cre mice had severe macrothrombocytopenia with moderately accelerated platelet clearance. Dnm2-null bone marrow MKs had altered demarcation membrane system formation in vivo due to defective endocytic pathway, and fetal liver-derived Dnm2-null MKs formed proplatelets poorly in vitro, showing that DNM2-dependent endocytosis plays a major role in MK membrane formation and thrombopoiesis. Endocytosis of the thrombopoietin receptor Mpl was impaired in Dnm2-null platelets, causing constitutive phosphorylation of the tyrosine kinase JAK2 and elevated circulating thrombopoietin levels. MK-specific DNM2 deletion severely disrupted bone marrow homeostasis, as reflected by marked expansion of hematopoietic stem and progenitor cells, MK hyperplasia, myelofibrosis, and consequent extramedullary hematopoiesis and splenomegaly. Taken together, our data demonstrate that unrestrained MK growth and proliferation results in rapid myelofibrosis and establishes a previously unrecognized role for DNM2-dependent endocytosis in megakaryopoiesis, thrombopoiesis, and bone marrow homeostasis.

Distinct effects of concomitant Jak2V617F expression and Tet2 loss in mice promote disease progression in myeloproliferative neoplasms.

Signaling mutations (eg, JAK2V617F) and mutations in genes involved in epigenetic regulation (eg, TET2) are the most common cooccurring classes of mutations in myeloproliferative neoplasms (MPNs). Clinical correlative studies have demonstrated that TET2 mutations are enriched in more advanced phases of MPNs such as myelofibrosis and leukemic transformation, suggesting that they may cooperate with JAK2V617F to promote disease progression. To dissect the effects of concomitant Jak2V617F expression and Tet2 loss within distinct hematopoietic compartments in vivo, we generated Jak2V617F/Tet2 compound mutant genetic mice. We found that the combination of Jak2V617F expression and Tet2 loss resulted in a more florid MPN phenotype than that seen with either allele alone. Concordant with this, we found that Tet2 deletion conferred a strong functional competitive advantage to Jak2V617F-mutant hematopoietic stem cells (HSCs). Transcriptional profiling revealed that both Jak2V617F expression and Tet2 loss were associated with distinct and nonoverlapping gene expression signatures within the HSC compartment. In aggregate, our findings indicate that Tet2 loss drives clonal dominance in HSCs, and Jak2V617F expression causes expansion of downstream precursor cell populations, resulting in disease progression through combinatorial effects. This work provides insight into the functional consequences of JAK2V617F-TET2 comutation in MPNs, particularly as it pertains to HSCs.

The POU factor ventral veins lacking/Drifter directs the timing of metamorphosis through ecdysteroid and juvenile hormone signaling.

Although endocrine changes are known to modulate the timing of major developmental transitions, the genetic mechanisms underlying these changes remain poorly understood. In insects, two developmental hormones, juvenile hormone (JH) and ecdysteroids, are coordinated with each other to induce developmental changes associated with metamorphosis. However, the regulation underlying the coordination of JH and ecdysteroid synthesis remains elusive. Here, we examined the function of a homolog of the vertebrate POU domain protein, Ventral veins lacking (Vvl)/Drifter, in regulating both of these hormonal pathways in the red flour beetle, Tribolium castaneum (Tenebrionidae). RNA interference-mediated silencing of vvl expression led to both precocious metamorphosis and inhibition of molting in the larva. Ectopic application of a JH analog on vvl knockdown larvae delayed the onset of metamorphosis and led to a prolonged larval stage, indicating that Vvl acts upstream of JH signaling. Accordingly, vvl knockdown also reduced the expression of a JH biosynthesis gene, JH acid methyltransferase 3 (jhamt3). In addition, ecdysone titer and the expression of the ecdysone response gene, hormone receptor 3 (HR3), were reduced in vvl knockdown larvae. The expression of the ecdysone biosynthesis gene phantom (phm) and spook (spo) were reduced in vvl knockdown larvae in the anterior and posterior halves, respectively, indicating that Vvl might influence ecdysone biosynthesis in both the prothoracic gland and additional endocrine sources. Injection of 20-hydroxyecdysone (20E) into vvl knockdown larvae could restore the expression of HR3 although molting was never restored. These findings suggest that Vvl coordinates both JH and ecdysteroid biosynthesis as well as molting behavior to influence molting and the timing of metamorphosis. Thus, in both vertebrates and insects, POU factors modulate the production of major neuroendocrine regulators during sexual maturation.

The treatment patterns, efficacy, and safety of nab (®)-paclitaxel for the treatment of metastatic breast cancer in the United States: results from health insurance claims analysis.

BACKGROUND: nab-Paclitaxel is an albumin-bound formulation of paclitaxel approved for the treatment of metastatic breast cancer (MBC). This analysis was designed to characterize the treatment patterns, efficacy, and safety of nab-paclitaxel for MBC treatment using health claims data from US health plans associated with Optum. METHODS: Women aged ≥ 18 years who initiated nab-paclitaxel for MBC treatment from January 1, 2005, to September 30, 2012, and who met eligibility criteria were selected from the Optum Research Database for this analysis. Patients were required to have complete medical coverage and pharmacy benefits, ≥ 6 months of continuous enrollment, and a diagnosis of MBC prior to nab-paclitaxel initiation. The pattern of use for nab-paclitaxel (eg, regimen, schedule, duration, and administration) and claims-captured toxicities were characterized by line of therapy. Overall survival (OS) and time to next therapy or death (TNTD) were described by line of therapy, regimen, and schedule. RESULTS: Of the 664 nab-paclitaxel patients, 172 (25.9%) received it as first-line therapy, 211 (31.8%) as second-line therapy, and 281 (42.3%) as third-line or later therapy. Overall, the majority of patients received monotherapy (61%) and followed a weekly (71%) rather than an every 3 weeks treatment schedule. nab-Paclitaxel was often (31.7%) combined with targeted therapy (57.5% with bevacizumab and 23.9% with trastuzumab or lapatinib). The median duration of therapy was 128 days (4.2 months). For the overall population, median OS was 17.4 months (22.7, 17.4, and 15.1 months in first-, second-, and third-line or later therapy, respectively). Median TNTD was 6.1 months (7.1, 6.6, and 5.3 months in first-, second-, and third-line or later therapy, respectively). For patients aged ≤ 50 years or with ≥ 3 metastatic sites, median OS was 15.6 months. No new safety signal was identified. CONCLUSIONS: In this US healthcare system, the majority of patients received nab-paclitaxel as second-line or later therapy, monotherapy, and weekly treatment. The efficacy and safety outcomes of nab-paclitaxel observed in this real-world setting appear consistent with those from clinical trial data.

Supportive Care Needs in Chinese, Vietnamese, and Korean Americans With Metastatic Cancer: Mixed Methods Protocol for the DAWN Study.

BACKGROUND: Asian Americans with metastatic cancer are an understudied population. The Describing Asian American Well-Being and Needs in Cancer (DAWN) Study was designed to understand the supportive care needs of Chinese-, Vietnamese-, and Korean-descent (CVK) patients with metastatic cancer. OBJECTIVE: This study aims to present the DAWN Study protocol involving a primarily qualitative, convergent, mixed methods study from multiple perspectives (patients or survivors, caregivers, and health care professionals). METHODS: CVK Americans diagnosed with solid-tumor metastatic cancer and their caregivers were recruited nationwide through various means (registries, community outreach newsletters, newspapers, radio advertisements, etc). Potentially eligible individuals were screened and consented on the web or through a phone interview. The study survey and interview for patients or survivors and caregivers were provided in English, traditional/simplified Chinese and Cantonese/Mandarin, Vietnamese, and Korean, and examined factors related to facing metastatic cancer, including quality of life, cultural values, coping, and cancer-related symptoms. Community-based organizations assisted in recruiting participants, developing and translating study materials, and connecting the team to individuals for conducting interviews in Asian languages. Health care professionals who have experience working with CVK patients or survivors with metastatic solid cancer were recruited through referrals from the DAWN Study community advisory board and were interviewed to understand unmet supportive care needs. RESULTS: Recruitment began in November 2020; data collection was completed in October 2022. A total of 66 patients or survivors, 13 caregivers, and 15 health care professionals completed all portions of the study. We completed data management in December 2023 and will submit results for patients or survivors and caregivers to publication outlets in 2024. CONCLUSIONS: Future findings related to this protocol will describe and understand the supportive care needs of CVK patients or survivors with metastatic cancer and will help develop culturally appropriate psychosocial interventions that target known predictors of unmet supportive care needs in Chinese, Vietnamese, and Korean Americans with metastatic cancer. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): DERR1-10.2196/50032.

Utilizing the Four Tenets of Osteopathic Medicine as an intersectional framework for approaching sexual orientation and gender identity disclosure as a provider.

The Lesbian, Gay, Bisexual, Transgender, Queer, Intersex, and other (LGBTQI+) community continues to experience health inequity and unmet needs. This manuscript examines the application of the Four Tenets of Osteopathic Medicine (FTOM) during a patient's self-disclosure of their sexual orientation and/or gender identity to the provider, also known as coming out. Tenet One discusses the interplay between intersectionality and coming out. Tenet Two elucidates how coming out moves toward a balance of homeostasis and self-healing. Tenet Three examines how structure and function can be understood on a personal level and how society influences coming out. Tenet Four explains the resources available to facilitate the previously forementioned changes. By applying the Four Tenets, the provider may more readily understand what "coming out" means on personal and social levels and what implications they may have on their patients' health.

Joint Estimation of Pedigrees and Effective Population Size Using Markov Chain Monte Carlo.

Pedigrees provide the genealogical relationships among individuals at a fine resolution and serve an important function in many areas of genetic studies. One such use of pedigree information is in the estimation of the short-term effective population size [Formula: see text], which is of great relevance in fields such as conservation genetics. Despite the usefulness of pedigrees, however, they are often an unknown parameter and must be inferred from genetic data. In this study, we present a Bayesian method to jointly estimate pedigrees and [Formula: see text] from genetic markers using Markov Chain Monte Carlo. Our method supports analysis of a large number of markers and individuals within a single generation with the use of a composite likelihood, which significantly increases computational efficiency. We show, on simulated data, that our method is able to jointly estimate relationships up to first cousins and [Formula: see text] with high accuracy. We also apply the method on a real dataset of house sparrows to reconstruct their previously unreported pedigree.

nab-Paclitaxel/carboplatin in elderly patients with advanced squamous non-small cell lung cancer: a retrospective analysis of a Phase III trial.

BACKGROUND: Limited data on elderly patients with squamous advanced non-small cell lung cancer (NSCLC) preclude optimal treatment. Here, we report the outcomes of a retrospective analysis of a subset of patients ≥70 years with squamous histology from the Phase III trial that evaluated nab-paclitaxel/carboplatin vs paclitaxel/carboplatin. PATIENTS AND METHODS: Patients with stage IIIB/IV NSCLC received (1:1) nab-paclitaxel 100 mg/m2 on days 1, 8, and 15 or paclitaxel 200 mg/m2 on day 1, both with carboplatin area under the curve 6 mg×min/mL on day 1 every 3 weeks. The primary endpoint was independently assessed overall response rate as per the Response Evaluation Criteria in Solid Tumors v1.0. Secondary endpoints included progression-free survival, overall survival, and safety. RESULTS: Sixty-five patients ≥70 years with squamous histology were included (nab-paclitaxel/carboplatin, n=35; paclitaxel/carboplatin, n=30). nab-Paclitaxel/carboplatin vs paclitaxel/carboplatin, respectively, resulted in an overall response rate of 46% vs 20% (response rate ratio, 2.29, P=0.029) and a median overall survival of 16.9 vs 8.6 months (hazard ratio, 0.50, P=0.018). No difference was observed in median progression-free survival (5.7 months for both). Incidences of grade 3/4 neutropenia (50% vs 63%), leukopenia (29% vs 37%), fatigue (3% vs 13%), and peripheral neuropathy (3% vs 13%) were lower, but those of thrombocytopenia (21% vs 10%) and anemia (21% vs 7%) were higher with nab-paclitaxel/carboplatin vs paclitaxel/carboplatin. CONCLUSION: nab-Paclitaxel/carboplatin was efficacious and tolerable in patients ≥70 years with squamous NSCLC. These results build upon prior analyses, indicating that nab-paclitaxel/carboplatin is effective for this difficult-to-treat patient subgroup.

Quality-Adjusted Survival With nab-Paclitaxel Versus Standard Paclitaxel in Metastatic Breast Cancer: A Q-TWiST Analysis.

BACKGROUND: In this analysis we compared quality-adjusted survival outcomes between nab-paclitaxel (nab-P) and standard paclitaxel (Pac) using data from the nab-P phase III registration trial in metastatic breast cancer. PATIENTS AND METHODS: Quality-adjusted overall survival was estimated using the quality-adjusted time without symptoms or toxicity (Q-TWiST) approach. Overall survival was partitioned into time without progression/Grade ≥ 3 adverse events (AEs) toxicity (TWiST), time with Grade ≥ 3 AE toxicity (TOX), and time after relapse (REL). Q-TWiST was calculated by multiplying mean time in each health state by its assigned utility (base-case utility values: time without symptoms of disease progression or toxicity of Grade ≥ 3 adverse events [TWiST] = 1.0, TOX = 0.5, and REL = 0.5). In threshold analyses, TOX and REL varied from 0.0 to 1.0 whereas TWiST was maintained at 1.0. Comparisons were made for the intent-to-treat population and the subset of patients initiating the study drugs as second or subsequent lines (2L+) of chemotherapy (per approved nab-P indication; 2L+ subpopulation). A ≥ 15% relative Q-TWiST gain (vs. mean Pac overall survival) was considered clearly clinically important. RESULTS: In the intent-to-treat population, nab-P (n = 229) versus Pac (n = 225) resulted in nonsignificant gains of 1.4 months of mean Q-TWiST (11.6 vs. 10.2 months; 95% confidence interval [CI], -0.03 to 2.8). In the 2L+ subpopulation, nab-P (n = 132) versus Pac (n = 136) resulted in a statistically significant gain of 2.2 months of mean Q-TWiST (10.5 vs. 8.4 months; 95% CI, 0.6-3.8), with a 17.1% relative Q-TWiST gain (threshold analysis range, 14.0%-19.5%, both figures significant). CONCLUSION: In its approved indication for metastatic breast cancer, nab-P showed a statistically significant and clearly clinically important improvement in quality-adjusted survival time versus Pac in the 2L+ subpopulation.

Robust Analysis of Fluxes in Genome-Scale Metabolic Pathways.

Constraint-based optimization, such as flux balance analysis (FBA), has become a standard systems-biology computational method to study cellular metabolisms that are assumed to be in a steady state of optimal growth. The methods are based on optimization while assuming (i) equilibrium of a linear system of ordinary differential equations, and (ii) deterministic data. However, the steady-state assumption is biologically imperfect, and several key stoichiometric coefficients are experimentally inferred from situations of inherent variation. We propose an approach that explicitly acknowledges heterogeneity and conducts a robust analysis of metabolic pathways (RAMP). The basic assumption of steady state is relaxed, and we model the innate heterogeneity of cells probabilistically. Our mathematical study of the stochastic problem shows that FBA is a limiting case of our RAMP method. Moreover, RAMP has the properties that: A) metabolic states are (Lipschitz) continuous with regards to the probabilistic modeling parameters, B) convergent metabolic states are solutions to the deterministic FBA paradigm as the stochastic elements dissipate, and C) RAMP can identify biologically tolerable diversity of a metabolic network in an optimized culture. We benchmark RAMP against traditional FBA on genome-scale metabolic reconstructed models of E. coli, calculating essential genes and comparing with experimental flux data.

nab-paclitaxel/carboplatin induction in squamous NSCLC: longitudinal quality of life while on chemotherapy.

BACKGROUND: Longitudinal data on the impact of treatment on quality of life (QoL) in advanced non-small cell lung cancer (NSCLC) are limited. In this palliative setting, treatment that does not deteriorate QoL is key. Here we report longitudinal QoL in patients with squamous NSCLC, receiving ≤4 cycles of nab-paclitaxel/carboplatin combination chemotherapy. METHODS: Patients received nab-paclitaxel 100 mg/m2 days 1, 8, 15 + carboplatin area under the curve 6 mg•min/mL day 1 (q3w) for four cycles. QoL was assessed by the Lung Cancer Symptom Scale (LCSS) and Euro-QoL-5 Dimensions-5 Levels (EQ-5D-5L) at baseline and each cycle (day 1). RESULTS: Two-hundred and six lesion-response-evaluable patients completed baseline + ≥1 postbaseline QoL assessment and were QoL evaluable. LCSS average total score and symptom burden index improved from baseline throughout four cycles. In the LCSS pulmonary symptoms score, 46% of patients reported clinically meaningful improvement (≥10 mm visual analog scale) from baseline. Individual EQ-5D-5L dimensions remained stable/improved in ≥83% of patients; ≈33% reported complete resolution of baseline problems at least once during four cycles. Generally, responders (unconfirmed complete/partial response) had higher scores vs nonresponders. CONCLUSION: In patients with squamous NSCLC, four cycles of nab-paclitaxel/carboplatin demonstrated clinically meaningful QoL improvements, with greater benefits in responders vs nonresponders.

Ancient genomes show social and reproductive behavior of early Upper Paleolithic foragers.

Present-day hunter-gatherers (HGs) live in multilevel social groups essential to sustain a population structure characterized by limited levels of within-band relatedness and inbreeding. When these wider social networks evolved among HGs is unknown. To investigate whether the contemporary HG strategy was already present in the Upper Paleolithic, we used complete genome sequences from Sunghir, a site dated to ~34,000 years before the present, containing multiple anatomically modern human individuals. We show that individuals at Sunghir derive from a population of small effective size, with limited kinship and levels of inbreeding similar to HG populations. Our findings suggest that Upper Paleolithic social organization was similar to that of living HGs, with limited relatedness within residential groups embedded in a larger mating network.