Robert Morris

Credit-based flow control for ATM networks

Simulation, analysis, and experiments on switching hardware have shown that for a wide variety of traffic patterns, credit control is fair, uses links efficiently, minimizes delay, and guarantees no cell loss due to congestion. The credit-based mechanism proposed by the authors provides flow control tailored to ATM networks. >

TCP behavior with many flows

TCPs ability to share a bottleneck fairly and efficiently decreases as the number of competing flows increases. This effect starts to appear when there are more flows, than packers in the delay-bandwidth product. In the limit of large numbers of flows, TCP forces a packet loss rate approaching 50%, causing delays that users are likely to notice. TCPs minimum congestion window of one packet is the source of these problems: it causes a few flows to send too fast while the rest wait in re-transmission time-out. The particular packet loss rate is a function of TCPs abrupt transition front exponential backoff to sending with a window of one or more packets, and of the high rate at which TCP increases small congestion windows. Analysis of packet traces suggests that these aspects of TCPs algorithms contribute substantially to the total loss rate observed on the Internet. One way to work around the problem is to make sure routers have not just one round-trip time of buffering, but buffering proportional to the total number of active flows. A more fundamental cure might make TCP less aggressive and more adaptive when its congestion window is small.

Scalable TCP congestion control

The packet losses imposed by IP networks can cause long and erratic recovery delays, since senders must often use conservative loss detection and retransmission mechanisms. This paper proposes a model to explain and predict loss rates for TCP traffic. Based on that model, the paper describes a new router buffering algorithm, flow-proportional queuing (FPQ), that handles heavy TCP loads without imposing high loss rates. FPQ controls TCP by varying the routers queue length in proportion to the number of active TCP connections. Simulation results show that FPQ produces the same average transfer delays as existing schemes, but makes the delays more predictable and fairer.

Variance of aggregated Web traffic

If data traffic were Poisson, increases in the amount of traffic aggregated on a network would rapidly decrease the relative size of bursts. The discovery of pervasive long-range dependence demonstrates that real network traffic is burstier than any possible Poisson model. We present evidence that, despite being non-Poisson, aggregating Web traffic causes it to smooth out as rapidly as Poisson traffic. That is, the relationship between changes in mean bandwidth and changes in variance is the same for Web traffic as it is for Poisson traffic. We derive our evidence from traces of real traffic in two ways: first, by observing how variance changes over the large range of mean bandwidths present in 24-hour traces; second, by observing the relationship of variance and mean bandwidth for individual users and combinations of users. Our conclusion, that variance changes linearly with mean bandwidth, should be useful (and encouraging) to anyone provisioning a network for a large aggregate load of Web traffic.

Proteomic analysis of pRb loss highlights a signature of decreased mitochondrial oxidative phosphorylation

The retinoblastoma tumor suppressor (pRb) protein associates with chromatin and regulates gene expression. Numerous studies have identified Rb-dependent RNA signatures, but the proteomic effects of Rb loss are largely unexplored. We acutely ablated Rb in adult mice and conducted a quantitative analysis of RNA and proteomic changes in the colon and lungs, where Rb(KO) was sufficient or insufficient to induce ectopic proliferation, respectively. As expected, Rb(KO) caused similar increases in classic pRb/E2F-regulated transcripts in both tissues, but, unexpectedly, their protein products increased only in the colon, consistent with its increased proliferative index. Thus, these protein changes induced by Rb loss are coupled with proliferation but uncoupled from transcription. The proteomic changes in common between Rb(KO) tissues showed a striking decrease in proteins with mitochondrial functions. Accordingly, RB1 inactivation in human cells decreased both mitochondrial mass and oxidative phosphorylation (OXPHOS) function. RB(KO) cells showed decreased mitochondrial respiratory capacity and the accumulation of hypopolarized mitochondria. Additionally, RB/Rb loss altered mitochondrial pyruvate oxidation from (13)C-glucose through the TCA cycle in mouse tissues and cultured cells. Consequently, RB(KO) cells have an enhanced sensitivity to mitochondrial stress conditions. In summary, proteomic analyses provide a new perspective on Rb/RB1 mutation, highlighting the importance of pRb for mitochondrial function and suggesting vulnerabilities for treatment.

Ultrarapid opioid detoxification : effects on cardiopulmonary physiology, stress hormones and clinical outcomes

This study explored the acute and long-term consequences of ultrarapid opioid detoxification (URD) in individuals with opioid dependence. In an open case series, seven patients underwent URD and subsequent treatment with daily naltrexone. Structured interviews, integrated rehabilitation and hair sampling were employed in the 12-week course of longitudinal follow-up. Cardiac and pulmonary physiology did not change significantly during the anesthesia phase of URD, but plasma ACTH and cortisol levels increased 15- and 13-fold, respectively. Marked withdrawal and tachypnea in all patients and respiratory distress in one patient occurred during the acute post-anesthesia phase. Withdrawal scores were significantly elevated for 3 weeks compared with baseline in the face of minimal self-reported craving for opioids. Anxiety, depression and vegetative symptoms improved gradually. Four patients remained abstinent of opioid use, two reported a brief period of opioid intake and one relapsed into daily opioid consumption. Given its effect on breathing and stress hormones, this procedure should be conducted by experienced anesthesiologists. The fact that URD and subsequent naltrexone treatment appears to cause a dissociation effect in the usual relationship between withdrawal and craving has implications for behavioral pharmacology. Further research is needed on the efficacy, safety, mechanisms and neurobiological sequelae of the procedure.

Bioengineered implantable scaffolds as a tool to study stromal-derived factors in metastatic cancer models

Modeling the hematogenous spread of cancer cells to distant organs poses one of the greatest challenges in the study of human metastasis. Both tumor cell-intrinsic properties as well as interactions with reactive stromal cells contribute to this process, but identification of relevant stromal signals has been hampered by the lack of models allowing characterization of the metastatic niche. Here, we describe an implantable bioengineered scaffold, amenable to in vivo imaging, ex vivo manipulation, and serial transplantation for the continuous study of human metastasis in mice. Orthotopic or systemic inoculation of tagged human cancer cells into the mouse leads to the release of circulating tumor cells into the vasculature, which seed the scaffold, initiating a metastatic tumor focus. Mouse stromal cells can be readily recovered and profiled, revealing differential expression of cytokines, such as IL1β, from tumor-bearing versus unseeded scaffolds. Finally, this platform can be used to test the effect of drugs on suppressing initiation of metastatic lesions. This generalizable model to study cancer metastasis may thus identify key stromal-derived factors with important implications for basic and translational cancer research.

ATR inhibition disrupts rewired homologous recombination and fork protection pathways in PARP inhibitor-resistant BRCA-deficient cancer cells

Poly-(ADP-ribose) polymerase (PARP) inhibitors (PARPis) selectively kill BRCA1/2-deficient cells, but their efficacy in BRCA-deficient patients is limited by drug resistance. Here, we used derived cell lines and cells from patients to investigate how to overcome PARPi resistance. We found that the functions of BRCA1 in homologous recombination (HR) and replication fork protection are sequentially bypassed during the acquisition of PARPi resistance. Despite the lack of BRCA1, PARPi-resistant cells regain RAD51 loading to DNA double-stranded breaks (DSBs) and stalled replication forks, enabling two distinct mechanisms of PARPi resistance. Compared with BRCA1-proficient cells, PARPi-resistant BRCA1-deficient cells are increasingly dependent on ATR for survival. ATR inhibitors (ATRis) disrupt BRCA1-independent RAD51 loading to DSBs and stalled forks in PARPi-resistant BRCA1-deficient cells, overcoming both resistance mechanisms. In tumor cells derived from patients, ATRis also overcome the bypass of BRCA1/2 in fork protection. Thus, ATR inhibition is a unique strategy to overcome the PARPi resistance of BRCA-deficient cancers.

Genomic Instability Is Induced by Persistent Proliferation of Cells Undergoing Epithelial-to-Mesenchymal Transition

TGF-β secreted by tumor stroma induces epithelial-to-mesenchymal transition (EMT) in cancer cells, a reversible phenotype linked to cancer progression and drug resistance. However, exposure to stromal signals may also lead to heritable changes in cancer cells, which are poorly understood. We show that epithelial cells failing to undergo proliferation arrest during TGF-β-induced EMT sustain mitotic abnormalities due to failed cytokinesis, resulting in aneuploidy. This genomic instability is associated with the suppression of multiple nuclear envelope proteins implicated in mitotic regulation and is phenocopied by modulating the expression of LaminB1. While TGF-β-induced mitotic defects in proliferating cells are reversible upon its withdrawal, the acquired genomic abnormalities persist, leading to increased tumorigenic phenotypes. In metastatic breast cancer patients, increased mesenchymal marker expression within single circulating tumor cells is correlated with genomic instability. These observations identify a mechanism whereby microenvironment-derived signals trigger heritable genetic changes within cancer cells, contributing to tumor evolution.

Vulvar/vaginal Melanoma: An Updated Surveillance Epidemiology and End Results Database Review, Comparison With Cutaneous Melanoma and Significance of Racial Disparities

Objective We aimed to compare the differences in demographic features, clinicopathologic features, and survival in patients with vulvar/vaginal melanoma versus cutaneous melanoma with a special emphasis on race. Materials and Methods Data were obtained from the Surveillance Epidemiology and End Results database from 1973 to 2008. Kaplan-Meier curves and Cox multivariate model were used for statistical analysis. Results Seven hundred sixty-two patients with vulvar/vaginal melanoma and 55,485 patients with cutaneous melanoma patients were included in the study. Twenty-eight patients of the vulvar/vaginal group and 334 patients of the cutaneous group were black (3.6% vs 0.6%, respectively). The median age at the time of diagnosis was 68 years in the vulvar/vaginal group and 52 years in the cutaneous group (P < 0.0001). Three hundred fifty patients (45.9%) in the vulvar/vaginal and 46,499 patients (83.8%) in the cutaneous group presented with localized disease (P < 0.0001), whereas 64 patients (8.4%) in the vulvar/vaginal group and 1520 patients (2.7%) in cutaneous group presented with advanced disease (P = 0.0081). The median survival of the black patients was 16 months in the vulvar/vaginal group and 124 months in the cutaneous melanoma group (P < 0.0001). The median survival in the nonblack population was 39 months in the vulvar/vaginal group compared to 319 months in the cutaneous melanoma group (P <0.0001). In multivariate analysis performed for patients between 1988 and 2008, age, stage, and positive lymph nodes were negative independent prognostic factors for survival in vulvar/vaginal melanoma; whereas age, race, stage, radiation therapy, and lymph node positivity were negative prognostic factors in cutaneous melanoma. Conclusion These findings emphasize that cutaneous and vulvar/vaginal melanomas have different clinicopathologic features and survival patterns.