KRAS-mutation is a key driver of pancreatic cancer and PI3K pathway activity is an additional requirement for Kras-induced tumorigenesis. Clinical trials of PI3K pathway inhibitors in pancreatic ...cancer have shown limited responses. Understanding the molecular basis for this lack of efficacy may direct future treatment strategies with emerging PI3K inhibitors. We sought new therapeutic approaches that synergise with PI3K inhibitors through pooled CRISPR modifier genetic screening and a drug combination screen. ERBB-family receptor tyrosine kinase signalling and mTOR signalling were key modifiers of sensitivity to alpelisib and pictilisib. Inhibition of the ERBB-family or mTOR was synergistic with PI3K inhibition in spheroid, stromal co-cultures. Near-complete loss of ribosomal S6 phosphorylation was associated with synergy. Genetic alterations in the ERBB-PI3K signalling axis were associated with decreased survival of pancreatic cancer patients. Suppression of the PI3K/mTOR axis is potentiated by dual PI3K and ERBB family or mTOR inhibition. Surprisingly, despite the presence of oncogenic KRAS, thought to bestow independence from receptor tyrosine kinase signalling, inhibition of the ERBB family blocks downstream pathway activation and synergizes with PI3K inhibitors. Further exploration of these therapeutic combinations is warranted for the treatment of pancreatic cancer.
Relatlimab and nivolumab combination immunotherapy improves progression-free survival over nivolumab monotherapy in patients with unresectable advanced melanoma
. We investigated this regimen in ...patients with resectable clinical stage III or oligometastatic stage IV melanoma (NCT02519322). Patients received two neoadjuvant doses (nivolumab 480 mg and relatlimab 160 mg intravenously every 4 weeks) followed by surgery, and then ten doses of adjuvant combination therapy. The primary end point was pathologic complete response (pCR) rate
. The combination resulted in 57% pCR rate and 70% overall pathologic response rate among 30 patients treated. The radiographic response rate using Response Evaluation Criteria in Solid Tumors 1.1 was 57%. No grade 3-4 immune-related adverse events were observed in the neoadjuvant setting. The 1- and 2-year recurrence-free survival rate was 100% and 92% for patients with any pathologic response, compared to 88% and 55% for patients who did not have a pathologic response (P = 0.005). Increased immune cell infiltration at baseline, and decrease in M2 macrophages during treatment, were associated with pathologic response. Our results indicate that neoadjuvant relatlimab and nivolumab induces a high pCR rate. Safety during neoadjuvant therapy is favourable compared to other combination immunotherapy regimens. These data, in combination with the results of the RELATIVITY-047 trial
, provide further confirmation of the efficacy and safety of this new immunotherapy regimen.
The COVID-19 pandemic caused >1 million infections during January-March 2020. There is an urgent need for reliable antibody detection approaches to support diagnosis, vaccine development, safe ...release of individuals from quarantine, and population lock-down exit strategies. We set out to evaluate the performance of ELISA and lateral flow immunoassay (LFIA) devices.
We tested plasma for COVID (severe acute respiratory syndrome coronavirus 2; SARS-CoV-2) IgM and IgG antibodies by ELISA and using nine different LFIA devices. We used a panel of plasma samples from individuals who have had confirmed COVID infection based on a PCR result (n=40), and pre-pandemic negative control samples banked in the UK prior to December-2019 (n=142).
ELISA detected IgM or IgG in 34/40 individuals with a confirmed history of COVID infection (sensitivity 85%, 95%CI 70-94%), vs. 0/50 pre-pandemic controls (specificity 100% 95%CI 93-100%). IgG levels were detected in 31/31 COVID-positive individuals tested ≥10 days after symptom onset (sensitivity 100%, 95%CI 89-100%). IgG titres rose during the 3 weeks post symptom onset and began to fall by 8 weeks, but remained above the detection threshold. Point estimates for the sensitivity of LFIA devices ranged from 55-70% versus RT-PCR and 65-85% versus ELISA, with specificity 95-100% and 93-100% respectively. Within the limits of the study size, the performance of most LFIA devices was similar.
Currently available commercial LFIA devices do not perform sufficiently well for individual patient applications. However, ELISA can be calibrated to be specific for detecting and quantifying SARS-CoV-2 IgM and IgG and is highly sensitive for IgG from 10 days following first symptoms.
In 1957--long before colleges awarded degrees in creative
nonfiction and back when newspaper writing's reputation was tainted
by the fish it wrapped--Princeton began honoring talented literary
...journalists. Since then, fifty-nine of the finest, most dedicated,
and most decorated nonfiction writers have held the Ferris and
McGraw professorships. This monumental volume harbors their
favorite and often most influential works. Each contribution is
rewarding reading, and collectively the selections validate
journalism's ascent into the esteem of the academy and the reading
public. Necessarily eclectic and delightfully idiosyncratic, the
fifty-nine pieces are long and short, political and personal, comic
and deadly serious. Students will be provoked by William Greider's
pointed critique of the democracy industry, eerily entertained by
Leslie Cockburn's fraternization with the Cali cartel, inspired by
David K. Shipler's thoughts on race, unsettled by Haynes Johnson's
account of Bay of Pigs survivors, and moved by Lucinda Frank's
essay on a mother fighting to save a child born with birth defects.
Many of the essays are finely crafted portraits: Charlotte Grimes's
biography of her grandmother, Blair Clark's obituary for Robert
Lowell, and Jane Kramer's affecting story of a woman hero of the
French Resistance. Other contributions to savor include Harrison
Salisbury on the siege of Leningrad, Landon Jones on the 1950s,
Christopher Wren on Soviet mountaineering, James Gleick on
technology, Gloria Emerson on Vietnam, Gina Kolata on Fermat's last
theorem, and Roger Mudd on the media. Whether approached
chronologically, thematically, randomly, or, as the editors order
them, more intuitively, each suggests a perfect evening reading.
Designed for students as well as general readers, The Princeton
Anthology of Writing splendidly attests to the elegance,
eloquence, and endurance of fine nonfiction.
The echinocandins are a well-known class of lipopeptides characterized by their potent antifungal activity against Candida species. The mechanism of action of the echinocandins is generally thought ...to be the inhibition of beta-1,3-glucan synthesis, an important structural component in the cell wall of Candida species. Extensive structure-activity studies on the fatty acid side chain of echinocandin B (1) led to the preparation of the clinical candidate cilofungin (4). However, little is known about the cyclic peptide. We now report the preparation, by solid-phase synthesis, of a series of simplified analogs of cilofungin in which the unusual amino acids found in the echinocandins were replaced with more readily accessible natural amino acids. The solid-phase approach to the total synthesis of these analogs allowed us to conveniently explore structural modifications that could not be accomplished by chemical modification of the natural product. The simplest analog 5 showed no biological activity. Structural complexity was then returned to the system in a systematic fashion so as to reapproach the original cilofungin structure. Antifungal activity and the inhibition of beta-1,3-glucan synthesis were monitored at each step of the process, thereby revealing the basic structure-activity relationships of the amino acids and the minimal structural requirements for biological activity in the echinocandin ring system. The results suggests that the 3-hydroxy-4-methylproline residue enhances activity but the L-homotyrosine residue is crucial for both antifungal activity and the inhibition of beta-1,3-glucan synthesis.
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